Antimicrobial peptides for anticancer and antiviral therapy: last promising update

Abstract

Antimicrobial peptides (AMPs) are short sequences of amino acids, typically 6–50 residues long, that serve as a natural defense mechanism against viruses, cancer, and other pathogens. They function primarily by disrupting microbial membranes, modulating immune responses, or targeting intracellular processes, making them promising alternatives to traditional antibiotics amid rising antimicrobial resistance. While AMPs hold significant promise in addressing infectious diseases and cancerous growths, a number of hurdles exist which necessitate resolution to achieve their full functional capacity. Challenges like high toxicity, poor stability, limited cellular penetration, and costly synthesis have limited their clinical approval. This necessitates the critical prediction and sophisticated design of new AMPs. Modern advancements in deep learning have catalyzed a heightened focus on computational strategies for identifying peptide-based therapeutics. Furthermore, the utilization of emerging peptides, such as those derived from bacterial and fungal metabolites, constitutes a significant factor in this endeavor. In addition, it addresses the importance of advanced methodologies in the creation and exploration of novel antiviral and anticancer peptides. In this review, types of antiviral and anticancer peptides and their structures were discussed. Also, with a modern perspective, the involvement of artificial intelligence and microbial metabolites in reducing the antimicrobial limitations of peptides was studied.

Introduction

Cancer continues to be a formidable challenge to human health, posing a severe threat to survival worldwide. While chemotherapy, often combined with surgery or radiotherapy, has proven instrumental in extending the life expectancy of cancer patients, its limitations are significant. One major drawback is the non-specific nature of many chemotherapeutic drugs, which cannot distinguish between cancerous and rapidly dividing healthy cells, resulting in collateral damage and serious side effects [1–3]. Adding to these challenges is the ability of cancer cells to develop resistance through mechanisms such as drug inactivation or efflux, as well as alterations in target proteins and signaling pathways. This resistance diminishes the effectiveness of existing treatments, highlighting an urgent need for new therapeutic strategies [4, 5]. Additionally, viral infections present another major public health challenge due to their complex nature and potential for rapid spread across global populations. Although historical events, such as the 1918 influenza outbreak, illustrate the catastrophic impact viruses can have on humanity, recent epidemics, including H1N1 and SARS-CoV-2, continue to demonstrate our vulnerability when vaccines or antiviral therapies are unavailable [6–8].

Antimicrobial peptides (AMPs) are small molecules vital to the immune defense of most organisms, from bacteria to animals. With strong antibacterial, antifungal, and antiviral properties, AMPs are essential components of host defense peptides (HDPs), offering broad-spectrum protection against pathogens [8, 9]. Their mechanisms of action are diverse and include direct microbial killing, neutralization of lipopolysaccharides (LPS), anti-inflammatory effects, promotion of wound healing, chemoattraction, and immunoregulation. To understand these complex actions, several models, such as the barrel-stave model and the carpet-like model, have been developed to illustrate how AMPs interact with microbial membranes. The effectiveness of AMPs is also influenced by their physicochemical characteristics, such as net charge and hydrophobicity [10–13]. These attributes help explain why pathogenic bacteria find it challenging to develop resistance against them. As research advances, the strategic design and delivery of AMPs become increasingly important for maximizing their therapeutic potential. Furthermore, emerging evidence suggests that beyond their role in combating infections, AMPs also contribute significantly to immune and metabolic regulation within the host organism [14–16].

In some cases, AMPs may be toxic to the host, thus enabling new techniques and models to combat cancer and viral infections. New AMPs are essential, but their design is challenged by the absence of set structural patterns and preferred physicochemical traits. Machine learning (ML) and deep learning advances reshaped data-driven biological problem strategies, facilitating rapid AMP detection [17]. A variational autoencoder (VAE) was utilized by some researchers, to produce new AMPs [18]. Furthermore, natural language models tailored for protein domains, encompassing techniques like LSTM and attention, have notably contributed to capturing the distinct features of AMPs. The application of GANs has provided considerable advancements in biological investigations, specifically by optimizing AMP design and genomics. Among the notable applications are PepGAN, capable of synthesizing AMPs, and WGAN-driven structures employed for constructing DNA sequences with specific properties [19].

Metabolites produced by fungi, especially secondary compounds originating from mushrooms and endophytic fungi, have been subjected to considerable investigation regarding their antiviral capabilities [20]. The specified constituents, notably polysaccharides, triterpenoids, and small organic molecules, display diverse antiviral effects targeting both lipid-enveloped and non-enveloped viral agents. Another aspect reveals the gut microbiota, a complex microbial array, forming diverse metabolites through fermenting food, host items, and microbe activity. Crucially, metabolites including bile acids, short-chain fatty acids (SCFAs), and tryptophan derivatives play key roles in host immune modulation, gut barrier preservation, and disease impact [20, 21]. Evidence indicates they can tackle both viral illnesses and cancer, largely by managing inflammation, interferon signaling, and immune system activation. AMPs, short cationic proteins from gut microbes, show broad efficacy against pathogens, including viruses and cancer cells. Microbiota-derived AMPs, like bacteriocins, display selective toxicity and immune modulation, offering therapeutic promise [22].

The administration of liver-expressed antimicrobial peptide 2 (LEAP2) leads to a decrease in post-meal plasma glucose levels and food consumption among healthy males, highlighting its significance in the regulation of metabolism. These changes occur via the growth hormone secretagogue receptor (GHSR), as indicated by the absence of these effects in GHSR-deficient mice, which suggests the receptor’s fundamental role. Beyond metabolic benefits, some AMPs, such as bacteriocins and caerins, hold potential for cancer treatment [23, 24]. Their antitumor properties are rooted in mechanisms like the induction of apoptosis and interference with the cancer cell cycle. This dual functionality of AMPs underscores their versatility, offering pathways to both enhance metabolic health and provide therapeutic avenues for combating certain types of cancers. As research progresses, these peptides could become integral components of innovative treatments across diverse medical fields [25, 26].

AMPs are emerging as potent therapeutic agents with the dual ability to combat viral infections and cancerous tumors. The mechanisms through which AMPs exert these effects include disrupting cell membranes and modulating immune responses, which are crucial for their therapeutic potential [27, 28]. Furthermore, advancements in AMP modifications have enhanced their stability and efficacy. Research into AMPs that possess dual functions against viruses and cancer is particularly encouraging for the development of effective treatments that can address several health risks concurrently, hinting at a future where specialized therapies deliver comprehensive solutions for multifaceted health problems. This review provides an update of AMPs, focusing on their antiviral and anticancer properties. Through the interplay of microbial metabolic profiles and artificial intelligence frameworks, the detection of novel AMPs can be significantly hastened, thereby advancing the development of antimicrobial drugs, a critical necessity given the persistent threat of therapeutic recalcitrance. This strategy improves the fidelity of AMP development and additionally increases the range of their potential uses, which is fundamentally important in addressing antimicrobial resistance.

Antimicrobial peptides characteristics and structure

The classification criteria for AMPs include amino acid sequences, net charge, protein structure, and their respective sources (Table 1). The majority typically possess an overall charge ranging from + 2 to + 9 and are composed of 10 to 100 amino acid residues. DBAASP (https://dbaasp.org/), known as the Database of Antimicrobial Activity and Structure of Peptides, is a publicly available platform that catalogs over 15,700 items in its third release [29].

Table 1.

Source and structure of antimicrobial peptides

Antimicrobial peptides name	Source	Structure	Sequence of amino acids	References
Antimicrobial peptide with anionic structure
ADP-2	Amblyomma hebraeum	Bridge	YENPYGCPTDEGKCFDRCNDSEFEGGYCGGSYRATCVCYRT	[29, 153]
Bb-AMP4	Snail	Unknown	PSCVCSGFETSGIHFC	[29, 154]
Beta2-microglobulin	Human	β-sheet	IQRTPKIQVYSRHPAENGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEKDEYACRVNHVTLSQPKIVKWDRDM	[29, 155]
Beta-amyloid peptide (1–40)	Human	Helix	DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA	[29, 156]
Chromacin	Bovine	Unknown	YPGPQAKEDSEGPSQGPASREK	[29, 157]
DCD-1	Human	Helix	SSLLEKGLDGAKKAVGGLGKLGKDAVEDLESVGKGAVHDVKDVLDSV	[29, 158]
Enkelytin	Bovine	Unknown	FAEPLPSEEEGESYSKEPPEMEKRYGGFM	[29, 159]
Kalata B10	Plant	Bridge	GLPTCGETCFGGTCNTPGCSCSSWPICTRD	[29, 160]
Maximin H5	Frog	Unknown	ILGPVLGLVSDTLDDVLGIL	[29, 161]
Microcin J25	Bacteria	β-sheet	GGAGHVPEYFVGIGTPISFYG	[29, 162]
Palicourein	Plant	Helix and β-sheet	GDPTFCGETCRVIPVCTYSAALGCTCDDRSDGLCKRN	[29, 163]
PvD1	Plant	Bridge	KTCENLADTYKGPCFTTGSCD	[29, 164]
Thuricin CD	Bacillus thuringiensis	Helix	GNAACVIGCIGSCVISEGIGSLVGTAFTLG	[29, 165]
Tricyclic peptide RP 71,955	Bacteria	β-sheet	CLGIGSCNDFAGCGYAVVCFW	[29, 166]
Antimicrobial peptide with Cation α-helix structure
BMAP-27	Bovine	Helix	GRFKRFRKKFKKLFKKLSPVIPLLHL	[29, 167]
Buforin II	Frog	Helix	TRSSRAGLQFPVGRVHRLLRK	[29, 168]
CAP18	Rabbit	Helix	GLRKRLRKFRNKIKEKLKKIGQKIQGFVPKLAPRTDY	[29, 169]
Cecropin A	Insect	Helix	KWKLFKKIEKVGQNIRDGIIKAGPAVAVVGQATQIAK	[29, 170]
Cecropin P1	Pig	Helix	SWLSKTAKKLENSAKKRISEGIAIAIQGGPR	[29, 171]
Ceratotoxin A	Fly	Helix	SIGSALKKALPVAKKIGKIALPIAKAALP	[29, 172]
Chrysophsin-1	Fish	Helix	FFGWLIKGAIHAGKAIHGLIHRRRH	[29, 173]
Crabrolin	Hornet	Helix	FLPLILRKIVTAL	[29, 174]
Figainin 2	Frog	Helix	FLGAILKIGHALAKTVLPMVTNAFKPKQ	[29, 175]
Human calcitermin	Human	Helix	VAIALKAAHYHTHKE	[29, 176]
LL-37	Human	Helix	LLGDFFRKAREKIGEEFKRIVQRIKDFLRNLVPRTES	[29, 177]
Magainin II	Frog	Helix	GIGKFLHSAKKFGKAFVGEIMNS	[29, 178]
mCRAMP	Mouse	Helix	GLLRKGGEKIGEKLKKIGQKIKNFFQKLVPQPEQ	[29, 179]
Melittin	Honeybee	Helix	GIGAVLKVLTTGLPALISWIKRKRQQ	[29, 180]
ModoCath1	Mouse	Helix	VKRTKRGARRGLTKVLKKIFGSIVKKAVSKGV	[29, 181]
Pleurocidin	Fish	Helix	GWGSFFKKAAHVGKHVGKAALTHYL	[29, 182]
SMAP-29	Sheep	Helix	RGLRRLGRKIAHGVKKYGPTVLRIIRIAG	[29, 183]
Temporin-PTa	Frog	Helix	FFGSVLKLIPKIL	[29, 184]
Antimicrobial peptide with Cation β-sheet structure
AvBD2	Chicken	β-sheet	LFCKGGSCHFGGCPSHLIKVGSCFGFRSCCKWPWNA	[29, 185]
Drosomycin	Fruitfly	Helix and β-sheet	DCLSGRYKGPCAVWDNETCRRVCKEEGRSSGHCSPSLKCWCEGC	[29, 186]
Gramicidin S	Bacteria	β-sheet	VKLFPVKLFP	[29, 187]
HBD1	Human	Helix and β-sheet	DHYNCVSSGGQCLYSACPIFTKIQGTCYRGKAKCCK	[29, 188]
HD5	Human	β-sheet	ATCYCRTGRCATRESLSGVCEISGRLYRLCCR	[29, 189]
Hepcidin	Fish	Bridge	CRFCCRCCPRMRGCGLCCRF	[29, 190]
HNP1	Human	β-sheet	ACYCRIPACIAGERRYGTCIYQGRLWAFCC	[29, 191]
Human drosomycin-like defensin	Human	Bridge	CLAGRLDKQCTCRRSQPSRRSGHEVGRPSPHCGPSRQCGCHMD	[29, 192]
Lactococcin 972	Lactococcus lactis	β-sheet	EGTWQHGYGVSSAYSNYHHGSKTHSATVVNNNTGRQGKDTQRAGVWAKATVGRNLTEKASFYYNFW	[29, 193]
mBD-7	Mouse	Helix and β-sheet	NSKRACYREGGECLQRCIGLFHKIGTCNFRFKCCKFQ	[29, 194]
Plectasin	Fungi	Helix and β-sheet	GFGCNGPWDEDDMQCHNHCKSIKGYKGGYCAKGGFVCKCY	[29, 195]
Protegrin 1	Pig	β-sheet	RGGRLCYCRRRFCVCVGR	[29, 196]
RNase 3	Human	Helix and β-sheet	RPPQFTRAQWFAIQHISLNPPRCTIAMRAINNYRWRCKNQNTFLRTTFANVVNVCGNQSIRCPHNRTLNNCHRSRFRVPLLHCDLINPGAQNISNCTYADRPGRRFYVVACDNRDPRDSPRYPVVPVHLDTTI	[29, 197]
RTD-2	Monkey	Bridge	GVCRCLCRRGVCRCLCRR	[29, 198]
Tachyplesin I	Horseshoe crab	β-sheet	KWCFRVCYRGICYRRCR	[29, 199]
THP-2	Bird	Bridge	LFCKRGTCHFGRCPSHLIKVGSCFGFRSCCKWPWDA	[29, 200]
Antimicrobial peptide with special amino acids structure
Alloferon 2	Fly	Unknown	GVSGHGQHGVHG	[29, 201]
Cateslytin	Human	Unknown	RSMRLSFRARGYGFR	[29, 202]
Cathelicidin-DM	Toad	Unknown	SSRRKPCKGWLCKLKLRGGYTLIGSATNLNRPTYVRA	[29, 203]
Citrocin	Bacteria	β-sheet	GGVGKIIEYFIGGGVGRYG	[29, 204]
Cp1	Bovine	Unknown	LRLKKYKVPQL	[29, 205]
dCATH	Bird	Helix	KRFWQLVPLAIKIYRAWKRR	[29, 206]
Hemoglobin	Bovine	Unknown	FLSFPTTKTYFPHFDLSHGSAQVKGHGAK	[29, 207]
Hg-CATH	Rat	Unknown	RRFRRTVGLSKFFRKARKKLGKGLQKIKNVLRKYLPRPQYAYA	[29, 208]
Histatins 1	Human	Rich	DSHEKRHHGYRRKFHEKHHSHREFPFYGDYGSNYLYDN	[29, 209]
Histone	Fish	Unknown	AERVGAGAPVYL	[29, 210]
Indolicidin	Bovine	Non-helix and β-sheet	ILPWKWPWWPWRR	[29, 211]
Lactoferricin	Human	Helix	GRRRRSVQWCAVSQPEATKCFQWQRNMRKVRGPPVSCIKRDSPIQCIQA	[29, 212]
Mytichitin-CB	Mollusca	Bridge	TVKCGMNGKMPCKHGAFYTDTCDKNVFYRCVWGRPVKKHCGRGLVWNPRGFCDYA	[29, 213]
Nemuri	Drosophila	Rich	DARARRIVRAGRRRGGRRGGRRGGRRSARKS	[29, 214]
PcAst-1a	Crawfish	Rich	SNGYRPAYRPAYRPSYRPGK	[29, 215]
Piscidin-1	Fish	Rich	FFHHIFRGIVHVGKTIHRLVTG	[29, 216]
PR-39	Pig	Rich	RRRPRPPYLPRPRPPPFFPP RLPPRIPPGFPPRFPPRFP	[29, 217]
Prophenin-1	Pig	Rich	AFPPPNVPGPRFPPPNFPGPRFPPPNFPGPRFPPPNFPGPRFPPPNFPGPPFPPPIFPGPWFPPPPPFRPPPFGPPRFP	[29, 218]
Pyrrhocoricin	Insect	Non-helix and β-sheet	VDKGSYLPRPTPPRPIYNRN	[29, 219]
Serrulin	Scorpion	Rich	GFGGGRGGFGGGRGGFGGGGIGGGGFGGGYGGGKIKG	[29, 220]
sfTSLP	Human	Unknown	MFAMKTKAALAIWCPGYSETQINATQAMKKRRKRKVTTNKCLEQVSQLQGLWRRFNRPLLKQQ	[29, 221]
SM-985	Plant	Rich	GAGIGPGHRRTWRRWPRRRWR	[29, 222]
Spgly-AMP	Crab	Non-helix and β-sheet	AIPAVDPFGRVKRSPWHGGTWGCKPIWACQNSPPYLG	[29, 223]
Thrombin	Human	Unknown	NLPIVERPVCKDSTRIRITDNMFCAGYKPDEGKRGDACEGDSGGPFVMKSPFNNRWYQMGIVSWGEGCDRDGKYGFYTHVFRLKKWIQKVIDQFGE	[29, 224]
Tur1A	Dolphin	Rich	RRIRFRPPYLPRPGRRPRFPPPFPIPRIPRIP	[29, 225]
Vipericidin	Snake	Unknown	TRSRWRRFIRGAGRFARRYGWRIALGLVG	[29, 226]

One subgroup: Among the various classifications, anionic AMPs form a specific subgroup, possessing a net charge from − 1 to − 8 and comprising 5 to 70 amino acids. The majority of these entities are peptide segments produced through proteolysis or diminutive molecules whose synthesis is genetically determined. Comprising amphibian α-helical peptides and cyclic cystine knots, these structures leverage metal ions for their engagement with microbial membranes, facilitated by salt bridges. An illustration is the ovine pulmonary surfactant-associated anion peptide (SAAP), possessing 5–7 aspartate residues, that displayed inhibitory effects on Mannheimia haemolytica when zinc ions were co-present. The presence of NaCl and EDTA resulted in the impairment of its antimicrobial function, a condition that was ameliorated by ZnCl2. Concurrently, the tilted α-helix structure of α-helical AMP maximin H5 is solidified by the amidated C-terminal fragment, which establishes intra-peptide hydrogen bonds involving its N-terminal region [29, 30].

Comprising the second subgroup are cationic \u03b1-helical AMPs, identified as small peptides with a length of under 40 amino acid residues, displaying a net positive charge between + 2 and + 9, and frequently having an amidated carboxy-terminal end. These peptides are unstructured in aqueous solutions; however, they acquire an α-helical conformation when trifluoroethanol, SDS micelles, phospholipid vesicles, or liposomes are present. Their structure is commonly characterized by more than 50% hydrophobic amino acids, thereby facilitating amphiphilic binding to specific cellular targets. A significant proportion of cathelicidins are characterized as amphiphilic α-helical AMPs, among which cecropins, magainins, and LL-37 are well-documented. Derived from hCAP18 by serine protease 3 within neutrophils, LL-37 is the singular human cathelicidin and is characterized by a net positive charge of + 6 at neutral pH levels. Findings from circular dichroism illustrate that in an aqueous environment, LL-37 remains unstructured, however, it develops a helical conformation under conditions where HCO3, SO42, or CF3CO2 are at a concentration of 15 mmol/L; the efficiency of this conversion is amplified as the peptide concentration rises. A correlation exists between the level of α-helix formation and LL-37’s antibacterial potency towards Gram-positive and Gram-negative bacterial species [29, 31].

Structure and function primarily define cationic β-sheet AMPs, the third AMP group. To achieve stability and function, these peptides require 1–4 disulfide bonds from 2 to 8 cysteines. Acidic amino acid substitution for cysteines inactivates peptides; hydrophobic amino acid changes retain function. Certain defensins (HNP1, HBD3, mouse) don’t need structures or disulfide bonds for antimicrobial function. β-sheet AMPs are primarily defensins, subdivided into α and β types based on six cysteine residue spacing and disulfide patterns [29, 30, 32]. Mammalian defensins, despite structural variance, possess similar tertiary forms. Hydrogen bonding between a β-hairpin and a three-stranded chain at the α-defensin amino terminus facilitates a cyclic structure via cysteine-disulfide bonds. Positive charges and hydrophobic amino acids enable them to disrupt bacterial membranes. The N-terminal domain mediates the antibacterial properties of β-defensins, including insect defensin A (which contains α-helix and β-sheet elements), while the C-terminal enhances them; antiviral activity necessitates the full protein [29, 32]. θ-defensins are cyclized tetracyclic peptides with three disulfide links between antiparallel β-sheets. Crucial for their antimicrobial traits, this cyclic structure permits high-salt activity, but its removal reduces microbicidal effects. Disulfide bond number and position largely dictate defensin structure and stability; antibacterial action stems from their cyclic backbone [29, 33].

Extended cationic AMPs, which are abundant in amino acids such as arginine, proline, tryptophan, glycine, and histidine, but do not possess typical secondary structures, form the fourth subgroup. The robustness they exhibit is contingent upon hydrogen bonds and van der Waals forces acting on membrane lipids. Antimicrobial protein fragments showing wide bactericidal action make up the fifth subgroup. Essential for innate immunity combating pathogens, lysozyme was the initial antimicrobial protein identified [29, 32]. Its 130-amino acid outer fragment exhibits α-helical and β-sheet folds. Human and chicken lysozymes contain an HLH region also found in diverse membrane-active proteins. HLH peptide effectively targets Gram-positive/negative bacteria and Candida albicans. The NEMURI protein, encoded by a recently found sleep-inducing gene in fruit flies, features an arginine-rich region with immunomodulatory and significant bactericidal effects, akin to kanamycin [29]. Other antibacterial proteins are listed in Table 1. Table 1.

Classification of antimicrobial peptides

Anticancer peptides

Studies highlight AMPs’ promise in anticancer therapies, focusing on their development. Repurposing AMPs into ACPs is gaining attention for selectively targeting cancer cells, sparing healthy tissue—an advantage over traditional treatments. Besides impacting tumors directly, AMPs modulate immune responses to enhance treatment efficacy [34]. For instance, human neutrophil peptide 1 (HNP-1) promotes dendritic cell maturation and activates Plasmacytoid dendritic cells through key pathways like NF-κB and IRF1, strengthening natural tumor defenses and synergizing with immunotherapies. Studies show that AMPs effectively inhibit tumor growth and induce apoptosis, suggesting they can integrate well into oncology regimens. As research progresses, AMP applications may lead to significant advancements in cancer therapies globally [35, 36].

Anticancer peptides in human

Pancreatic cancer is inhibited by LL-37, causing DNA damage and cell cycle arrest through mTOR. A hostile environment for cancer cells arises from mitochondrial dysfunction and ROS accumulation. Through MDSC and M2 macrophage reduction, LL-37 affects the tumor microenvironment, boosting T-cell anticancer action. Beyond pancreatic cancer, LL-37 shows broad-spectrum anticancer effects across various malignancies, making it a versatile therapeutic agent [36, 37]. However, in human primary lung tumors, LL-37 from myeloid cells can promote tumor growth through Wnt/β-catenin signaling via PKB/AKT and GSK3β phosphorylation mediated by TLR-4 pathways. This dual nature highlights the complexity of LL-37 in different cancers and emphasizes developing targeted therapies that consider its diverse mechanisms across tumor types [38].

Anticancer peptides in bovine and mouse

Figure 1 shows Lactoferricin B (LfcinB) is noted for its anticancer properties, particularly in breast cancer cell lines. LfcinB impairs the invasive properties of MDA-MB-231 and MDA-MB-468, potentially hindering metastasis. In vivo studies reveal intratumor LfcinB injections reduce tumor volume and weight in mouse xenograft models using MDA-MB-231-GFP-luc2 cells [39]. Additionally, it shows efficacy against cisplatin-resistant head and neck squamous cell carcinoma (HNSCC), reducing tumor volumes in xenografted mice models by suppressing pro-inflammatory cytokines like IL-6 and immune checkpoint proteins such as PD-L1. Mouse calethicidin-related antimicrobial peptide (mCRAMP) maintains innate immunity by protecting colon mucosa integrity and ensuring gut microbiota balance; CRAMP-deficient mice are more susceptible to colitis from dextran sulfate sodium (DSS) and carcinogenesis by azoxymethane, underscoring these peptides’ protective roles in controlling inflammation and preventing cancer in epithelial tissues [40–42].

Fig. 1.

Antiviral peptides from different hosts or synthetic peptides

Anticancer peptides in other eukaryotic

Recent studies have highlighted the anticancer properties of Ascaphin-8 and its analog, Ascaphin-8–3, which inhibit cancer cell proliferation, particularly against lung adenocarcinoma A549 cells. Figainin 2 shows promise due to its cationic and hydrophobic nature, affecting breast cancer MCF-7 and melanoma B16F10 cells while activating ROS production in neutrophils. Magainin 2 also exhibits activity against leukemia and ovarian cancer. These findings underscore their potential in developing new cancer therapies to improve outcomes across various malignancies [43, 44].

Piscidin-1, a potent antimicrobial peptide, induces apoptosis in osteosarcoma cells by disrupting mitochondrial function. It alters mitochondrial ROS levels, decreases antioxidant manganese superoxide dismutase, and reduces ATP synthesis to promote cell death. Piscidin-1 specifically targets human lung adenocarcinoma (A549) and ovarian cancer cells (SKOV-3), sparing healthy ones, making it a promising targeted cancer treatment with minimal side effects. Plant-based peptides like defensins and cyclotides also show potential in combating cancer. Cyclotides display cytotoxicity against HCT 116 colorectal carcinoma and MCF-7 breast adenocarcinoma cell lines [27, 45]. These findings suggest that marine-derived peptides like Piscidin-1 and plant-derived AMPs could revolutionize cancer treatment by selectively targeting cancer cells while preserving healthy tissue integrity. Melittin from bee venom inhibits melanoma growth via apoptosis through caspase activation and pathway disruption (PI3K/AKT/mTOR and MAPK). Protein Y3 from Coprinus comatus mushrooms also shows promise against Jurkat leukemia cells by inducing caspase-dependent apoptosis, demonstrating the potential of natural substances in developing targeted cancer therapies [27, 46].

Anticancer peptides in bacteria

Gramicidin A, a potent ionophore, is gaining attention for its role in inhibiting various cancer cells. In MCF-7 breast cancer cells, it disrupts ion balance and induces mitochondrial depolarization, inhibiting ATP generation and cell proliferation. In cholangiocarcinoma cells, it impedes growth by suppressing early growth response protein 4 (EGR-4) expression. As shown in Fig. 1, in gastric cancer lines like SGC-7901 and BGC-823, Gramicidin A induces apoptosis by inhibiting the G2/M phase and reducing phosphorylation of Forkhead Box O1 (FOXO1), B-cell lymphoma-2 (Bcl-2), and cyclin D1. It also shows efficacy in pancreatic cancer models BxPC-3 and MIA PaCa-2 by downregulating CD47 levels. These findings highlight Gramicidin A’s potential as an anticancer agent targeting multiple pathways to induce apoptosis and inhibit tumor growth across diverse cancers [47, 48].

Synthetic AMPs

In Fig. 1, the synthetic peptide CAMEL (CM15, KWKLFKKIGAVLKVL-NH2), derived from cecropin A and melittin, is noteworthy for its ability to disrupt mitochondrial function by penetrating cellular membranes. Once inside, it induces organelle swelling and inhibits ATP production, leading to cell lysis. This mechanism underscores its potential as a therapeutic agent due to its ability to target and dismantle essential cellular structures. Additionally, when combined with stearic acid (C18), CAMEL effectively delivers p53 plasmids into cancer cells. This combination significantly boosts the expression of p53—a vital tumor suppressor gene—resulting in decreased cell proliferation and presenting a promising avenue for cancer treatment strategies. By harnessing these properties, researchers can explore innovative applications for CAMEL in oncological therapies aimed at controlling and potentially eliminating malignant cells through targeted molecular interventions [27, 49] Fig. 1.

Antiviral peptides

AMPs are gaining recognition not only for their potent antibacterial properties but also for their broad-spectrum antiviral activities against enveloped viruses. These peptides, such as bovine antimicrobial peptide-13, demonstrate remarkable efficacy by disrupting viral protein synthesis and gene expression, effectively inhibiting the proliferation of viruses like the transmissible gastroenteritis virus [50, 51]. We showed in Table 2 that, their versatility is further exemplified by AMPs like protegrin and indolicidin, which exhibit anti-herpes simplex virus (HSV) activity through mechanisms that block viral adhesion and entry by targeting viral membrane glycoproteins. Moreover, LL-37 demonstrates its antiviral prowess against a range of enveloped viruses, including the human immunodeficiency virus (HIV) and the Zika virus (ZIKV), by compromising the integrity of viral membranes and halting DNA replication processes. Interestingly, LL-37, alongside mouse CRAMP, also demonstrates effectiveness against non-enveloped viruses, such as enterovirus 71, by modulating antiviral responses and preventing viral binding. Through these multifaceted actions, AMPs represent a promising frontier in antiviral therapies with potential applications across a wide array of viral infections [52, 53].

Table 2.

Antimicrobial peptides with anticancer properties

Peptides	Sources	Cancers	Mechanisms and futures	References
LL-37	Human	Gastric cancer, Colon cancer, Pancreatic cancer, Hematologic malignancy, Glioblastoma, Oral squamous cell, carcinoma	Inducing DNA damage and cell cycle arrest through mTOR signaling activation raises concerns. The mTOR pathway regulates cell growth, but deliberately activating it could harm healthy cells, causing tissue damage or inflammation. Additionally, activating the Wnt/β-catenin pathway complicates matters, as it is crucial for cell fate and development; its uncontrolled activation in adults is linked to cancer progression. This method assumes precise control over complex systems, often beyond current capabilities. Potential off-target effects highlight the need for careful consideration before clinical use.	[27]
Lactoferricin B	Bovine	Head and neck squamous cell carcinoma (HNSCC), Breast cancers,	Inducing cancer cell apoptosis and suppressing IL-6 and PD-L1 expression are promising cancer treatment strategies, but they face challenges. Inducing apoptosis requires precise targeting to avoid harming healthy cells. Suppressing IL-6 and PD-L1 is difficult due to their roles in immune function. IL-6 aids immune responses but can also promote tumor growth if overexpressed, while PD-L1 is crucial in preventing autoimmunity. Thus, translating these ideas into effective therapies involves significant hurdles in specificity, safety, and side effects.	[27]
mCRAMP	Mouse	Colon cancer	Maintaining colon mucosal homeostasis and preventing diseases like DSS-induced colitis and azoxymethane-mediated carcinogenesis are complex. Despite many studies proposing solutions, practical application often falls short due to human biology’s intricacies. Relying on DSS as an inflammation model may not fully replicate human conditions, leading to misleading efficacy conclusions. Similarly, translating azoxymethane research findings to clinical practice requires careful consideration of model limitations and relevance.	[27]
Ascaphin-8 and its analogs	Frog	Lung adenocarcinoma	Inhibiting cell proliferation and cancer metastasis is a major challenge in oncology. Despite medical advances, effectively targeting and preventing rapid cell division and spread remains difficult. Current therapies like chemotherapy and radiation often harm healthy cells, causing severe side effects that affect patient quality of life. Cancer’s ability to resist these treatments further complicates long-term suppression or eradication. This underscores the need for innovative approaches that precisely target malignant cells without harming normal ones, highlighting the importance of ongoing research in cancer treatment.	[27]
Magainin 2		Leukemia, Ovarian cancer	To induce cancer cell death.	[27]
Piscidin-1	Fish	Osteosarcoma, Lung adenocarcinoma	To induce cell apoptosis by regulating the production of mitochondrial reactive oxygen species (ROS) and reducing mitochondrial antioxidant manganese superoxide dismutase and adenosine 5′-triphosphate production, resulting in mitochondrial dysfunction.	[27]
Cyclotides and cycloviolacins	Plant	Colorectal carcinoma, Breast adenocarcinoma	To induce cancer cell death.	[27]
Melittin	Insect	Melanoma	To induce cell apoptosis effectively, enhancing caspase 3 and 9 activation is crucial. These enzymes dismantle cellular components in the apoptotic process. However, it’s also necessary to suppress survival pathways like PI3K/AKT/mTOR and MAPK, which promote cell survival and proliferation. Effective strategies must address both activators and inhibitors for a comprehensive approach. Additionally, there’s debate about whether current methods target these pathways without affecting normal cells, posing a challenge in therapy.	[27]
Protein Y3	Fungi	T cell leukemia	To induce caspase-dependent cell apoptosis	[27]
Gramicidin A	Bacteria	Gastric cancer, Breast cancer, Pancreatic cancer	To inhibit cell proliferation—uncontrolled cell growth and division—strategies must target cellular mechanisms responsible for rapid expansion. Inducing apoptosis, or programmed cell death, maintains tissue health and prevents cancer by removing damaged cells without inflammation. Downregulating CD47 expression is crucial since this protein signals immune cells to ignore harmful cells. Lowering CD47 enhances the immune system’s ability to detect and eliminate these problematic cells. These processes are key in therapies against diseases with abnormal cell growth and survival.	[27]
CAMEL	Synthetic	Cancer cell lines, such as HepG2, Hela, MB-MDA-231, MCF-7, and B16.	To increase p53 expression and suppress cell proliferation.	[27]

Studies highlight AMPs’ crucial role in altering immune responses and enhancing protection against viral infections. For example, AMPs like Pa-MAP and temporin B reduce HSV1 infection by blocking virus attachment to host cells. Temporin B also destroys the viral envelope, affecting post-infection stages for multi-layered defense. Temporin G interacts with influenza virus hemagglutinin protein, blocking vital changes in the HA2 subunit necessary for entry, and it inhibits parainfluenza replication by blocking release. AMPs like HD5 and cathelicidin-derived compounds such as GF-17 and BMAP-18 are key in fighting viral infections. HD5 effectively inhibits viral adherence and entry into host cells [54, 55].

Cathelicidin-derived AMPs inactivate viruses like ZIKV by interfering with the interferon pathway. Other AMPs target viruses such as dengue (DENV) and pseudorabies, while LL-37 addresses non-enveloped viruses like adenovirus and rhinovirus. These peptides disrupt viral particles and replication cycles, also modulating the host’s immune response to hinder viral growth. Vitamin D aids in producing cathelicidins and defensins, reducing virus replication rates for pathogens like influenza and COVID-19. This research underscores AMPs’ potential in enhancing immunity and targeting various viral life stages, presenting promising therapeutic avenues against many infections [56, 57].

Antiviral peptides in human

Human cathelicidin LL-37 emerges as a vital player in the body’s defense arsenal, particularly against viral infections such as HIV. This antimicrobial peptide not only inhibits viral replication but also modulates immune responses, underscoring its significance in preventing HIV progression. The expression of LL-37 is closely linked to Vitamin D levels, emphasizing the nutrient’s role in bolstering antiviral defenses. As shown in Table 2, beyond its anti-HIV prowess, LL-37 exhibits broad-spectrum antiviral activity against various pathogens, including West Nile virus (WNV), DENV, and Venezuelan equine encephalitis virus (VEEV). It shows promise against viruses such as HSV-1 and SARS-CoV-2. Alongside Human Neutrophil Peptide 1 (HNP-1), which is produced by neutrophils during pathogenic attacks, these peptides play a crucial role in the innate immune system’s response to diverse viral threats [51, 58, 59].

HNP1 disrupts SARS-CoV-2 by binding to its Spike protein, preventing attachment to ACE-2 receptors. It also inhibits HIV entry by blocking envelope glycoprotein interactions. During HIV infection, dendritic cells secrete HNP1-3 to neutralize virions. In pregnant women with COVID-19, increased HNP1 and β-defensins 1–4 correlate with higher IL-10 levels, suggesting enhanced protection. Genetic variations in the hBD-1 gene (DEFB1) are linked to decreased HIV susceptibility among Zambians, highlighting innate immunity’s role in viral resistance [58].

Antiviral peptides in bovine and mouse

In Table 2, lactoferricins, indolicidin, bovine myeloid antimicrobial peptides (BMAPs), and mouse cathelicidin-related antimicrobial peptides (mCRAMPs) are crucial in fighting infections. Indolicidin targets swine viruses like PRRSV, PEDV, TGEV, and is temperature-sensitive against HIV-1; its analogs inhibit VEEV through cytokines IL-1α/β and TNF. BMAPs such as BMAP-27, BMAP-28, BMAP-34 enhance immune responses; notably, BMAP-28 is linked to nervous system inflammation during alpha-herpesvirus infection. mCRAMP has antiviral properties against ZIKV; increased expression reduces infection severity while CRAMP deficiency worsens testicular damage. CRAMP-deficient mice have lower CD4 and CD8 T cells during MmuPV1 but benefit from synthetic CRAMP disrupting virion integrity. These peptides show promise as therapeutic agents by modulating immunity and inhibiting microbes [60, 61].

Antiviral peptides in other eukaryotic

Derived from the African clawed frog, Magainin 2 is an antimicrobial peptide that combats bacteria and viruses. It interacts with lipopolysaccharides (LPS) to form nanopores in lipid membranes, compromising cellular integrity. Magainin 2B has shown antiviral effects against the vaccinia virus by disrupting membrane integrity. In silico research suggests Magainins 1 and 2 may affect SARS-CoV-2, though more validation is needed. Amphibian peptides like Caerin 1. 1 block pseudorabies virus infections, while Temporins act against various pathogens, including HSV-1 and influenza, by targeting viral proteins. These findings highlight amphibian AMPs’ potential in developing antiviral medications [51, 62, 63].

Piscidin-1 is a potent antiviral agent effective against pseudorabies virus (PRV) and porcine epidemic diarrhea virus (PEDV). It has high bioavailability and favorable pharmacokinetics when injected intramuscularly, neutralizing PRV by binding to viral particles in vitro and in vivo. Tilapia hepcidin (TH) may reduce nervous necrosis virus (NNV) in medaka fish by inhibiting key molecular pathways like transforming growth factor beta-1 (TGF-β1), specificity protein 1 (SP1), nuclear factor (NF)-κB2, and interferon (IFN) [64, 65]. Epinecidin-1 (Epi-1) shows antiviral efficacy against foot-and-mouth disease virus (FMDV). Tachyplesin I from horseshoe crab hemocytes prevents infection by viruses such as red-spotted grouper nervous necrosis virus (RGNNV) and the Singapore grouper iridovirus (SGIV). These AMPs hold promise for enhancing antiviral treatments across species and advancing research against various viral threats [66, 67].

Plant bioactive compounds and natural peptides are drawing interest for their antibacterial, antiviral, and anticancer properties. Sesquin has antifungal and antibacterial abilities and inhibits HIV-1. Melittin from bee venom offers potent antibacterial and antiviral effects. Alloferon combats influenza virus infection and human herpesvirus replication. The fungal protein Y3 targets viral proteins, disrupting tobacco mosaic virus, while fungal defensins like plectasin enhance immune responses in chickens against E. coli, reducing inflammation. These compounds showcase nature’s potential to address health challenges effectively [68, 69].

Antiviral peptides in bacteria

The antibacterial efficacy of Gramicidin A arises from its ability to disrupt the ionic equilibrium of the cell membrane. Recent focus has shifted to Gramicidin S for its potential antiviral effects against SARS-CoV-2. Studies show it can significantly reduce viral load and enhance clearance in infected Vero cells, similar to melittin, another antiviral peptide. Furthermore, in silico analyses have demonstrated that Gramicidin S can bind effectively with the SARS-CoV-2 spike glycoprotein. This binding is crucial as it may inhibit viral infection by preventing the virus from attaching and entering host cells. These findings suggest that Gramicidin S could be a promising candidate for further research and development in antiviral therapies targeting COVID-19 [30, 67].

Synthetic antiviral peptides

Cecropin-melittin hybrid peptide (CAMEL) is a synthetic peptide with strong antibacterial properties, especially against anaerobic bacteria. In antiviral research, GF-17 shows promise in preventing and treating the ZIKV. This activity is partially attributed to its ability to activate type-I interferon (IFN) signaling, an essential component of the immune response. Additionally, the study highlights BAMP-18, a bovine-derived AMP, which mirrors GF-17’s impact against ZIKV, underscoring its potential as an effective antiviral agent. Together, these peptides exemplify the advancements in synthetic biology and immunotherapy, offering new avenues for addressing microbial infections and enhancing our understanding of immune activation mechanisms [29, 70].

Developing dual-function AMPs could improve treatments by targeting both viral and bacterial pathogens. This approach streamlines protocols and reduces antibiotic resistance risk from misuse in viral infections. Incorporating AMPs into antiviral treatments can boost efficacy, speed recovery, lower healthcare costs, and ease the strain on facilities during outbreaks. Investing in research to optimize these peptides strengthens defenses against pandemics and improves global health outcomes. Table 2 presents an overview of the mechanisms through which peptides exhibit anticancer properties [71, 72]. Table 2.

Mechanism of antimicrobial peptides against cancer cells

In Fig. 2, the unique cationic nature of AMPs makes them promising in cancer therapy by targeting cancer cells and disrupting their membranes, inducing apoptosis. This selectivity arises from the higher density of negatively charged particles on cancer cells and increased surface area due to villi. AMPs penetrate cancer cell membranes effectively, modulate immune responses by activating natural killer cells and macrophages, stimulate cytokine production, and inhibit angiogenesis. These mechanisms suggest AMPs can lead to innovative anticancer therapies that are precise and minimize damage to healthy tissues [73–75].

Fig. 2.

Schematic diagram of four widely recognized models of the membrane disruption mechanisms of Antimicrobial Peptides

AMPs are proving to be valuable in cancer treatment by specifically targeting and breaking down the membranes of cancerous cells. They interact with the negatively charged membranes of cancer cells, showcasing broad-spectrum anticancer properties. Unlike healthy cells, which have neutral charges, cancer cells are negatively charged due to the presence of anionic molecules, such as phosphatidylserine [76, 77]. This enhances AMP binding affinity to tumor cell membranes more than normal ones. The increased microvilli on tumor cells provide a larger surface for AMP interaction, promoting cytotoxic effects on cancerous tissues while sparing healthy ones. Additionally, AMPs act against multi-drug-resistant (MDR) tumors by reversing resistance through reduced P-glycoprotein activity and altering membrane dynamics, thus offering promising cancer treatment solutions without harming healthy tissue [78, 79].

Membrane mechanism

The intricate dance between AMPs and tumor cell membranes has captivated the scientific community, leading to the development of various theoretical models that seek to unravel this complex interaction. As shown in Fig. 2, among these are the “Aggregate,” “Toroidal-pore,” “Carpet,” and” Barrel-stave” models, each offering unique insights into how AMPs may disrupt or interact with cellular structures. These models highlight that AMPs do not operate in isolation; instead, their mechanisms can vary significantly depending on concentration and environmental conditions. This exploration into AMP behavior not only advances our understanding of cellular interactions but also holds potential implications for therapeutic strategies against cancer [80, 81].

The “Barrel-Stave” model offers a fascinating insight into how certain AMPs interact with tumor cell membranes. In this model, α-helix cationic AMPs, such as bee venom peptide and cecropin B, initiate their action by binding to the tumor cell membrane through electrostatic attraction. This initial binding is crucial as it sets the stage for the subsequent structural transformation of the AMPs. Once bound, these peptides undergo a conformational change that allows them to insert their hydrophobic regions perpendicularly into the membrane’s hydrophobic core [82, 83]. This insertion resembles “staves” in a barrel, hence the name of the model. The process of AMP monomer aggregation leads to the formation of an α-helix polymer, which features a hydrophilic side that creates a barrel-shaped hollow channel within the membrane. This structural formation leads to transient transmembrane pores that disrupt essential cellular processes by altering ion gradients and transmembrane potential, ultimately causing cell death. However, it is essential to note that this model has its limitations; it cannot account for membrane disruption by AMPs shorter than 23 amino acids, as they are unable to span the entire cell membrane effectively in this manner. Understanding these mechanisms highlights not only how AMPs can be potent antitumor agents but also underscores the complexity of interactions at play within cellular environments [84, 85]. Figure 2.

Non-membrane mechanisms

AMPs have emerged as a promising tool in the fight against cancer, primarily due to their ability to target and disrupt tumor cell membranes through electrostatic interactions. However, their anticancer potential extends beyond this primary mechanism. AMPs also engage in a variety of other actions that contribute to their effectiveness, including inhibiting DNA synthesis within tumor cells, dismantling the cytoskeleton, preventing angiogenesis, damaging mitochondria, and inducing apoptosis or necrosis. In Fig. 3, additionally, they play a role in modulating the immune response against tumors. This multifaceted approach highlights the versatility and potential of AMPs as powerful agents in cancer therapy [86, 87].

Fig. 3.

Anticancer peptides (ACPs) present a multifaceted approach to combating cancer, yet their effectiveness comes with complexities that warrant critical examination. While the primary mode of action for many ACPs revolves around electrostatic interactions with tumor cell membranes, leading to membrane disruption and subsequent cell death, this is only part of the story. These peptides also engage in a range of secondary mechanisms like inhibiting tumor DNA synthesis and destabilizing the tumor’s cytoskeleton, which complicates their role in oncological treatments. Additionally, ACPs have shown potential in suppressing tumor angiogenesis and destroying mitochondrial structures within cancer cells, thereby inducing apoptosis or necrosis. However, the diversity of these mechanisms raises questions about specificity and potential off-target effects in clinical settings. Moreover, while they can mediate immune responses and regulate intracellular signaling pathways to enhance anticancer activity, the intricacies involved pose challenges in understanding their full impact on both cancerous and healthy cells alike. Therefore, while ACPs offer promising avenues for cancer therapy through their various mechanisms, a deeper understanding is crucial to harness their full therapeutic potential without unintended consequences

Chromosomes and DNA damage

Some AMPs possess the capability to gather in the nuclei of malignant cells, triggering cell death by inflicting damage on the DNA of tumors. For example, Cecropin-XJ, derived from Xinjiang silkworms, binds to tumor DNA, disrupts the base pair arrangement, and loosens the helical structure, resulting in DNA damage and subsequent cell death. Research has demonstrated that CM4 from Bombyx mori can selectively break down the DNA of K562 cancer cells without affecting the DNA of normal cells [88, 89].

Cytoskeleton damage

The cell cytoskeleton maintains cell morphology and order. It is involved in various cellular activities, including movement, transport, communication, division, and gene expression. Eukaryotic cells possess a well-developed cytoskeleton comprising microfilaments and microtubules. Cancer cells have an underdeveloped system with fewer microfilaments and microtubules. Anticancer drugs target tubulin; AMPs can damage the cytoskeleton in both normal and cancerous cells. Normal cells can self-repair due to their complete cytoskeletons, unlike tumor cells, which can lead to their death. Studies show that AMPs-activated cecropins, specifically B3, disintegrate microtubules, disrupting the function and integrity of tumor cells [90–93].

Tumor angiogenesis Inhibition

AMPs are emerging as powerful cancer-fighting agents by inhibiting tumor growth and angiogenesis. Angiogenesis, necessary for tumor development and metastasis, is disrupted by AMPs like K6L9, which effectively kill tumor cells. Human α-defensins provide a multifaceted approach by binding to fibronectin (FN), blocking cell adhesion, and inhibiting VEGF-mediated proliferation of endothelial cells. This inhibits pathways crucial for tumor angiogenesis. AMPs highlight their potential as anticancer agents and open new avenues for therapeutic strategies targeting cancer’s vascular lifeline [16, 94, 95].

Mitochondria attacking and cancer

The role of AMPs in cancer therapy has emerged as significant, as they effectively induce cell death in tumors through processes such as apoptosis or necrosis. Pardaxin, an antimicrobial peptide sourced from marine environments, influences biological processes by interacting with the mitochondrial membrane. It plays a crucial role in lowering mitochondrial potential, thereby facilitating the release of cytochrome c and ROS, which are pivotal in the apoptotic mechanism. This event triggers the downstream activation of caspases 3 and 7, facilitating apoptosis through the intrinsic pathway, which is linked to the mitochondria [90, 96, 97]. In Fig. 3, Buforin II B, a significant antimicrobial peptide derived from histone H2A, distinguishes itself from numerous cytotoxic agents by penetrating the membranes of tumor cells without harming cellular structures. When it penetrates the cell, it prompts the release of cytochrome c and the activation of caspase-9, which in turn initiates the apoptotic process through the same mitochondrial pathway utilized by pardaxin. The findings demonstrate that AMPs can function as targeted therapeutic strategies, utilizing internal cellular mechanisms to specifically promote programmed cell death in tumor cells while minimizing the impact on normal tissue [98, 99].

Immunity regulation

The immune system relies heavily on AMPs, which not only serve to eliminate infections but also possess strong antitumor capabilities via immunomodulation. AMPs attract monocytes, DCs, T cells, and neutrophils into the tumor microenvironment, thereby enhancing the ability of antigen-presenting cells to capture tumor cells and augment the tumor’s immunogenic profile [96, 100, 101]. AMP LL-37 serves as a notable illustration, as it significantly suppresses tumor proliferation by promoting dendritic cell phagocytosis and enhancing the levels of phagocytic receptors and co-stimulatory molecules. In Fig. 3, the activation of this process amplifies the Th1 cell response. It elevates cytokine release, thereby fostering conditions that are less conducive to tumor development. By activating caspase-3 and poly (ADP-ribose) polymerase, Cecropin XJ induces apoptosis in liver cancer, demonstrating its anticancer potential and modulating the Bcl-2 family proteins. These results highlight the potential of AMPs in cancer treatment, as they effectively modulate immune responses to inhibit tumor growth and progression [98, 99]. Figure 3.

Tumor microenvironment

Cancer progression heavily relies on the tumor microenvironment, which enhances processes like angiogenesis and metastasis. The process of angiogenesis, or the formation of new blood vessels, is crucial for tumor development, as it ensures the supply of essential nutrients and oxygen. Metastasis involves the spread of cancer cells to distant sites, often leading to worsened prognoses. AMPs have emerged as promising agents in disrupting these processes, thereby enhancing cancer therapy. AMPs inhibit angiogenesis by specifically targeting endothelial cells that form the lining of new blood vessels, thereby effectively reducing the tumor’s blood supply and inducing conditions such as hypoxia and necrosis within the tumor mass [1, 16, 42].

Furthermore, AMPs impede metastasis by interfering with the interactions between cancer cells and the extracellular matrix, which is essential for their migration and invasion into other tissues. Beyond these actions, AMPs also target stromal cells in the tumor microenvironment, modulating immune responses by affecting regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), thereby boosting antitumor immunity and increasing therapeutic efficacy. Through these multifaceted mechanisms, AMPs offer a powerful approach to hindering cancer progression while supporting current therapeutic strategies [102–104].

Mechanisms of antimicrobial peptides against virus infections

Some AMPs exhibit antiviral activity against various viruses, including enveloped and non-enveloped types. Nine peptidomimetic drugs treat AIDS, with at least four under development for the influenza virus. Saquinavir, a protease inhibitor, mimics the peptide bond but resists breakdown by HIV-1 protease. AVPs target HIV by focusing on specific virus components, such as the fusion process and the protease enzyme [6, 105, 106].

Antimicrobial peptides against the HIV virus

AMPs inhibit HIV at various stages, including entry, replication, and release. A cationic 18-amino acid peptide impacts HIV-1 production in human cell lines. GRFT blocks CD4 receptor interactions and viral capsid glycoproteins to prevent entry. Kalata B1 covers the viral membrane surface to inhibit infection. Some AMPs target reverse transcriptases or integrases, crucial for integrating viral DNA; α-defensins can directly inactivate the virus. LL-37 delivers cGAMP to cells, triggering an interferon response via STING-dependent immunity [107, 108]. These mechanisms suggest that AMPs offer a multifaceted therapeutic approach against HIV with reduced drug resistance risks. Stelletapeptines reveal strong anti-HIV-1 properties; however, the detailed processes involved in their inhibition of viral entry are not fully elucidated. Recent findings suggest a significant role for anti-HIV antibodies in both in vitro and in vivo environments. The oral mouthwash formulation of PAC-113 has undergone and completed Phase II trials targeting HIV-positive patients suffering from oral candidiasis. The ongoing Phase III clinical trials for Sifuvirtide are evaluating the efficacy of administering 20 mg daily doses compared to administering 90 mg of enfuvirtide twice a day. Ongoing trials are investigating the safety, efficacy, and administration of AMP-based treatments as components of combination therapies, confirming their effectiveness against HIV and setting the stage for future investigations; nonetheless, additional clinical trials are necessary to validate the therapeutic potential of AMPs [109–111].

Antimicrobial peptides against the influenza virus

Influenza viruses are responsible for significant global respiratory infections, primarily due to their high mutation rates, which result in seasonal epidemics and severe pandemics. While vaccines play a crucial role in reducing the number of cases and slowing the spread of the virus, their development is complicated by the virus’s genetic instability. Current treatments, such as neuraminidase inhibitors, often fall short in effectiveness, highlighting the need for new antiviral strategies against the influenza A virus (IAV). AMPs (AMPs) are emerging as promising candidates because they can disrupt viral envelopes or capsids and modulate immune responses [72, 112]. Figure 4 shows us that, Flufirvitide impedes viral invasion; Esculentin-1GN and urumins block host cell attachment; LL-37 destabilizes membranes in IAV-infected mice; Caerin 1 inhibits HIV transmission with low toxicity. These characteristics suggest that AMPs could be instrumental in developing new influenza therapies capable of overcoming drug resistance across various subtypes [84, 113, 114].

Fig. 4.

Mechanism of actions of antimicrobial peptides (AMPs) against SARS-CoV-2. AMPs like Esculentin-1GN (E-1GN), Urumins, LL-37, and Caerin 1 have demonstrated promising antiviral properties that could potentially reshape the landscape of influenza therapies. However, critical examination reveals that while Esculentin-1GN and urumins effectively block host cell attachment of the virus, and LL-37 destabilizes membranes in influenza A virus (IAV)-infected mice, these findings are mostly confined to specific laboratory conditions. The leap from experimental success to practical application poses significant challenges due to potential variability in human response and the complex nature of viral mutations. Moreover, while Caerin 1’s ability to inhibit HIV transmission with low toxicity is noteworthy, translating similar efficacy against influenza remains an uncharted territory requiring rigorous testing and validation across diverse viral subtypes. The ambitious goal of overcoming drug resistance with AMPs also raises concerns about long-term effectiveness and potential side effects in humans. Thus, although AMPs offer a hopeful avenue for developing new therapies against resistant strains of influenza, there is a critical need for comprehensive research to address these complexities before they can be reliably integrated into clinical practice

Research on AMPs for anti-influenza therapy is advancing with promising results. A 27-amino acid peptide from human BPI disrupts the viral envelope and inhibits various influenza A virus (IAV) strains, unlike the mouse BPI peptide. TL peptide derivatives show significant antiviral efficacy against viruses like herpesviruses, paramyxoviruses, influenza viruses, and SARS-CoV-2. Lipidation modifications enhance these effects by improving membrane insertion and reducing cytotoxicity. In animal models, certain AMPs reduce viral loads and improve survival rates. Additionally, lactoferrin reduces intestinal damage in H5N1-infected mice due to its anti-inflammatory properties. Despite encouraging findings, clinical trials are in early stages; more research is needed to explore AMPs as a supplement or alternative to traditional therapies [115, 116] Fig. 4.

Antimicrobial peptides against SARS-CoV-2

Currently, there are no specific antiviral drugs or universal vaccines for coronaviruses. However, AMPs show significant promise due to their broad-spectrum antiviral properties. AMPs can disrupt viral envelopes and prevent coronavirus entry into host cells. Notably, the lipopeptide EK1C4 has been shown to effectively inhibit SARS-CoV-2 fusion and infection, surpassing its predecessor EK1 in mouse models.

Figure 5 shows that peptides target the virus and modulate the immune response, minimizing inflammation and lung injury. Defensins inhibit viral infection during cell entry and have anti-inflammatory effects by recruiting T cells and monocytes. Human defensin 5 (HD5) reduces viral load by associating with ACE2, activates immune phagocytes, and interferes with replication enzymes. Lactoferrin similarly prevents viral entry via ACE2. Plitidepsin is a potential COVID-19 treatment candidate by inhibiting eEF1A. AMPs may enhance other antiviral drugs; for example, vitamin D induces LL-37 expression to bind SARS-CoV-2’s S1 domain, masking ACE2 to limit infection [117–119]. AMPs could be key in developing broad-spectrum antivirals against coronaviruses. Research on AMPs against SARS-CoV-2 has intensified during the pandemic, identifying candidates that inhibit replication and reduce viral load in early studies. These findings highlight the need for more research into AMP-based therapies’ efficacy, safety, and delivery methods for treating current or future outbreaks [120, 121].

Fig. 5.

The mechanism of action of antimicrobial peptides (AMPs) in combating viruses, particularly SARS-CoV-2, is crucial yet complex, encompassing almost the entire viral life cycle. While they hold promise, a critical examination reveals both potential and limitations. AMPs like HD5, LL37, and HBD2 engage at various stages: they inhibit viral particles and prevent adsorption and entry by binding to ACE2 receptors, thereby blocking the virus’s ability to attach itself to host cells. However, the differential affinities with which these peptides bind pose a challenge; for instance, LL-37’s binding affinity to ACE2 is weaker compared to its interaction with the S-RBD protein on SARS-CoV-2. This raises questions about their efficacy in varying physiological conditions. Moreover, while Plitidepsin (APL) shows promise by targeting eEF1A in COVID-19 treatment strategies and lactoferrin (LF) aids in preventing viral entry via ACE2 interference, these approaches require rigorous evaluation for safety and effectiveness before widespread use. Thus, while AMPs offer exciting avenues for antiviral therapy against SARS-CoV-2, their diverse mechanisms demand thorough investigation to ascertain their role as reliable therapeutic agents in real-world applications

The COVID-19 pandemic has spurred research into AMPs as a defense against coronaviruses, such as SARS-CoV-2. Initial studies show that AMPs can inhibit viral replication and reduce viral load, offering hope for new treatments. These preliminary successes set the stage for further investigations into the efficacy, safety, and delivery of AMP therapies. This research is vital for developing treatments for current and future coronavirus outbreaks and enhancing global health security. The ongoing exploration of AMP-based solutions underscores a commitment to utilizing advanced science to combat pandemics and safeguard global public health [121, 122] Fig. 5.

Challenges and constraints of antimicrobial peptides in treating viral infections and cancer

The prevailing approach in antiviral research involves targeting one specific virus at a time, which encounters challenges from the quick mutation processes of viruses and the rise of escape mutants. Broad-spectrum antivirals are more effective against a diverse range of viruses. Although AMPs feature unique mechanisms and low resistance in innate immunity, they are hindered by challenges such as instability, host cell toxicity, high production expenses, and low in vivo potency, leading to few effective clinical trial results. Continued research is necessary to enhance the stability, safety, and cost-effectiveness of AMPs for viable antiviral therapy options [123, 124].

AMPs are at the forefront of research endeavors aimed at enhancing their clinical efficacy and maximizing their potential as antiviral therapies. Given the inherent challenges of developing antiviral drugs that are both effective and safe for host cells, AMPs are being studied intensively to understand their unique mechanisms of action better. Researchers are seeking to elucidate how these peptides interact with viral particles, disrupt viral replication, and modulate host immune responses without causing harm. Additionally, identifying synergistic effects between AMPs and other antiviral agents is a priority, as combining treatments could lead to more robust therapeutic outcomes. As investigations into the immunomodulatory properties of AMPs continue, there is optimism that they will become a vital component in the arsenal against viral diseases. Ultimately, by offering broad-spectrum activity with minimal side effects, AMPs hold great promise in advancing global health strategies for more effective antiviral therapy solutions.

AMPs have distinct mechanisms of action and low resistance, but their use in cancer treatment faces significant obstacles, primarily due to their breakdown and inactivation through interactions with negatively charged serum proteins. Their use in medical treatments is complicated by hemolytic toxicity and susceptibility to hydrolysis. It is vital to enhance the stability and effectiveness of AMPs and mitigate their adverse impacts, given that they struggle with challenges such as low stability, host cell toxicity, high production costs, and low in vivo potency, with only a few demonstrating clinical trial success [125–127]. One promising strategy involves optimizing their structure through targeted modifications, focusing on key elements such as amino acid substitution, cyclization, hybridization, and terminal modifications. These adjustments aim to enhance the stability, half-life, and specificity of the peptides. For instance, altering net positive charges can increase affinity for cancer cell membranes without excessively raising hydrophobicity, which could lead to unwanted hemolytic toxicity. Achieving an optimal balance among these factors is vital for enhancing AMP activity against cancer cells while ensuring safety in clinical settings. By carefully designing these modifications based on structure-activity relationships, researchers hope to unlock the full potential of AMPs as effective anticancer agents with minimized side effects [126–128].

Future directions and research needs

Reducing toxicity and increasing efficiency

To fully harness the potential of AMPs as groundbreaking cancer therapies, several pivotal research areas must be prioritized. To improve the stability and effectiveness of AMPs, it is crucial to optimize their structural and functional traits by modifying peptide sequences and developing fusion proteins that enhance resistance to degradation while reducing toxicity [127, 128]. Furthermore, it is essential to develop innovative delivery methods that ensure AMPs specifically target cancer cells while minimizing their impact on healthy tissues. Cutting-edge delivery techniques, including nanotechnology and liposomal carriers, enhance the targeting of tumors while minimizing side effects; the inclusion of specific ligands can further increase targeting accuracy. Moreover, exploring synergistic combination therapies holds great promise for enhancing the therapeutic impact of AMPs when used in conjunction with traditional treatments, such as chemotherapy, radiotherapy, or immunotherapy. By addressing these research areas comprehensively, we can move closer to realizing the full potential of AMPs in revolutionizing cancer treatment strategies [129–132]. Future research should identify optimal combinations and explore synergistic effects through preclinical and clinical studies. Basic investigations into AMPs have been conducted; however, their anticancer functions are not fully understood, mainly due to a shortage of in vivo studies and a failure to correlate in vitro experiments with animal research. Improving research on pharmacokinetics and pharmacodynamics might connect in vitro stability with animal model bioavailability [131–133].

Sources of promising antimicrobial peptides (Anticancer and antiviral peptides)

Microbial metabolites

Microbe-derived metabolites are now seen as significant infection therapies in health and farming. Researchers explore microbial sources for drugs given natural compounds’ benefits over synthetic alternatives. These microbially-derived secondary compounds (MSMs) serve as fundamental materials in the formulation of drugs effective against a range of pathogens, including viruses, bacteria, fungi, and parasites. Table 3 highlights diverse microorganisms (bacteria, fungi, actinomycetes, microalgae) produce various antiviral metabolites, including quinones and alkaloids. Antivirals mainly originate from fungi, then bacteria and microalgae; marine environments yield many MSMs. Diverse antiviral functions are seen in these metabolites; their precise pathways remain unexplored. Knowing these mechanisms allows for effective drug development against viruses [134–136].

Table 3.

Bacterial and fungal metabolites against cancer and virus infections

Metabolite type	Sources	Antiviral and anticancer mechanisms	Key evidence and outcomes	References
Bacterial metabolites
Short-Chain Fatty Acids (SCFAs) (Examples: Acetate, Propionate, Butyrate)	Antiviral: Bifidobacterium, Faecalibacterium, Roseburia Anticancer: Bifidobacterium, Faecalibacterium, Roseburia	Antiviral: Activate GPR43/41 to promote type I IFN and ISG expression in lung epithelial cells, reducing viral load. Regulate inflammation via HDAC inhibition and NLRP3 inflammasome modulation. Enhance IgA secretion and Treg differentiation for mucosal protection. Anticancer: Inhibit HDACs to induce apoptosis and cell cycle arrest (G2/M phase). Enhance CD8 + T-cell function and DC maturation via GPR109A. - Reduce inflammation and tumor angiogenesis.	Antiviral: Acetate protects against rotavirus (RV) and respiratory syncytial virus (RSV) by GPR43-mediated IFN responses; high-fiber diets increase SCFA production, reducing RV load and inflammation in animal models. Butyrate limits influenza A virus (IAV) replication by priming myeloid cells for antiviral hematopoiesis. Dual effects: Low SCFAs may promote viral persistence in dysbiosis. Anticancer: Butyrate suppresses CRC proliferation via p53 activation; high SCFA levels correlate with better ICI response in melanoma. Dual effects: High systemic SCFAs may limit CTLA-4 blockade efficacy by Treg induction.	[27, 104, 137, 138]
Flavonoid Derivatives (Examples: Desaminotyrosine (DAT))	Antiviral: Clostridium orbiscindens Anticancer: ???	Antiviral: Enhances type I IFN signaling in macrophages via TLR7/9, protecting against influenza. Modulates distal lung immunity through gut-lung axis. Anticancer: ???	Antiviral: DAT from gut commensals reduces influenza severity in mice; antibiotic depletion abolishes protection. Proviral in some contexts (e.g., enhances enteric norovirus stability). Anticancer: ???	[27]
Bile Acids (Examples: Secondary bile acids (e.g., deoxycholic acid, lithocholic acid))	Antiviral: Clostridium, Bacteroides Anticancer: Clostridium scindens	Antiviral: Activate FXR/TGR5 receptors to regulate IFN responses and inflammasomes. Inhibit viral entry/replication in some viruses (e.g., norovirus). Anticancer: FXR activation inhibits proliferation; UDCA reduces inflammation. Modulate Tregs/Th17 balance to suppress tumor growth.	Antiviral: Bile acids from microbiota inhibit murine norovirus via FXR signaling; dysbiosis reduces this protection. Dual role: Some promote inflammation aiding viral spread in chronic infections. Anticancer: Secondary bile acids like DCA promote CRC at high levels but UDCA protects via FXR in HCC models.	[27, 104, 137, 138]
Tryptophan Metabolites (Examples: Indole, Indole-3-propionic acid (IPA))	Antiviral: Clostridium sporogenes, Bacteroides Anticancer: Lactobacillus reuteri, Clostridium	Antiviral: Activate AhR to enhance epithelial barrier and IL-22 production, limiting viral invasion. Modulate NLRP6 inflammasome for antiviral innate immunity. Anticancer: Activate AhR to boost IL-22 and barrier integrity, inhibiting tumor invasion. Enhance CD8 + T-cell infiltration and ICI efficacy.	Antiviral: Indole derivatives protect against influenza by boosting IFN-γ and Treg cells; microbiota depletion impairs this. Anticancer: IPA from Lactobacillus improves PD-1 blockade in CRC models; low IPA linked to poor prognosis. I3A restores mucosal integrity in liver fibrosis models.	[104, 137, 138]
Other Metabolites (Examples: Inosine, TMAO)	Antiviral: ??? Anticancer: Bifidobacterium pseudolongum	Antiviral: ??? Anticancer: Inosine via A2A receptor enhances T-cell priming for ICI synergy. TMAO promotes antitumor immunity in breast cancer via IFN-γ.	Antiviral: ??? Anticancer: Inosine boosts PD-1 efficacy in multiple cancers; Bifidobacterium colonization correlates with better outcomes.	[27]
Fungal metabolites
Polysaccharides	Antiviral: Ganoderma spp: HSV, Influenza Anticancer: ???	Antiviral: Immune modulation, viral attachment inhibition Anticancer: ???	Antiviral: Hinnuliquinone from fungal sources inhibits HIV-1 protease. Agrocybone from Agrocybe salicacola shows activity via inhibition of viral hemagglutinin. Anticancer: ???	[142, 143]
Cordycepin	Antiviral: Cordyceps militaris: SARS-CoV-2 Anticancer: ???	Antiviral: Mpro inhibition, poly(A) polymerase blockade Anticancer: ???	Antiviral: Sphaeropsidins A and B from phytopathogenic fungi reduce bovine coronavirus yield by deacidifying lysosomes and downregulating aryl hydrocarbon receptor signaling. Anticancer: ???	[142, 143]
Sphaeropsidins A/B	Antiviral: Diplodia spp: Bovine coronavirus Anticancer: ???	Antiviral: Lysosomal deacidification, AhR downregulation Anticancer: ???	Antiviral: ??? Anticancer: ???	[142, 143]
Hinnuliquinone	Antiviral: fungal dimeric non-peptide: HIV-1 Anticancer: ???	Antiviral: Protease inhibition Anticancer: ???	Antiviral: ??? Anticancer: ???
Ganoderic acids	Antiviral: ??? Anticancer: Ganoderma lucidum: Hepatocellular carcinoma	Antiviral: ??? Anticancer: ROS induction, apoptosis	Antiviral: ??? Anticancer: ???	[142, 143]
Pestheic acid	Antiviral: ??? Anticancer: Pestalotiopsis guepinii: Hepatocellular carcinoma	Antiviral: ??? Anticancer: Cytostatic, genotoxic	Antiviral: HSV, Influenza Anticancer: ???	[142, 143]
Simplicilliumtides	Antiviral: ??? Anticancer: Simplicillium obclavatum: Gastric adenocarcinoma	Antiviral: ??? Anticancer: Cytotoxicity (IC50 39–100 µM)	Antiviral: ??? Anticancer: ???	[142, 143]
Beauvericins	Antiviral: ??? Anticancer: Fusarium spp: Leukemia (HL-60, K562)	Antiviral: ??? Anticancer: Mycotoxic, pathway modulation	Antiviral: ??? Anticancer: ???	[142, 143]

Gut microbial metabolites as a new anticancer and antiviral

Metabolites originating from the gut microbiota permeate the intestinal epithelial barrier to enter systemic circulation, thereby modulating antiviral immune responses both locally (within the gut) and in distant organs (such as the lungs and liver). These compounds govern inflammatory processes, interferon signaling, and the initial activation of T-cells, frequently through their interaction with G-protein-coupled receptors (GPCRs) or pattern recognition receptors (PRRs). Short-chain fatty acids (SCFAs), which have been extensively investigated, are generated by bacterial phyla like Firmicutes and Bacteroidetes during the fermentation of dietary fibers [104, 137, 138].

As detailed in Table 3, the antiviral mechanisms involve metabolites such as SCFAs and DAT, which primarily augment innate immune responses, including type I IFN production via GPR43, and enhance adaptive immunity, such as CD8 + T-cell priming by dendritic cells. These molecules subsequently traverse the gut-lung axis to distant sites, leading to a reduction in viral load during respiratory infections. Disruptions in the microbiome, exemplified by antibiotic-induced dysbiosis, attenuate these beneficial outcomes, rendering individuals more susceptible to viral pathogens like influenza and norovirus. The clinical significance is underscored by the observation that high-fiber diets, which elevate SCFA levels, confer protection to newborns against RSV, indicating a potential role for dietary interventions in viral prevention [16, 139].

Gut microbial metabolites and their anticancer effects

The impact of microbial metabolites on carcinogenesis is multifaceted, involving direct cytotoxic effects, immunomodulatory actions, and alterations in epigenetic regulation (e.g., the inhibition of histone deacetylases). Table 3 highlights that SCFAs and tryptophan-derived compounds function as notable antitumoral agents, stimulating apoptosis and T-cell permeation while simultaneously restricting tumor expansion. Conversely, some of these compounds, specifically secondary bile acids, exhibit procarcinogenic properties at elevated concentrations [140, 141].

Regarding the molecular underpinnings of antineoplastic actions, metabolites like butyrate are known to inhibit HDACs, resulting in increased histone hyperacetylation and ultimately apoptosis in CRC cells. Beyond this, they remodel the TME by drawing in CD8 + T cells and DCs, a process that amplifies the potency of immune checkpoint blockade strategies (e.g., PD-1/PD-L1 inhibition). Tryptophan metabolites, acting through the AhR, are instrumental in promoting IL-22 for barrier protection and eliciting anti-tumor Th1 responses. Conversely, microbial dysbiosis leads to a scarcity of advantageous metabolites, worsening clinical trajectories; low concentrations of SCFAs, for example, are associated with resistance to chemotherapy. Clinically, diets abundant in fiber are linked to increased SCFA production, which in turn improves survival rates among melanoma patients receiving ICIs [16, 141].

Fungi metabolites as a new anticancer and antiviral

The virucidal potential of fungal metabolites, especially secondary compounds from mushrooms and endophytes, has been thoroughly investigated, revealing their broad efficacy against enveloped and non-enveloped viruses through components like polysaccharides, triterpenoids, and small organic molecules [142].

Certain medicinal fungi, exemplified by Ganoderma lucidum (Reishi) and Lentinula edodes (Shiitake), provide extracts rich in β-glucans and other polysaccharides that impede the replication of viruses through interference with their capacity for attachment and entry into cells. Specifically, Ganoderma polysaccharides have displayed antiviral activity against herpes simplex virus (HSV) and influenza, achieving this by adjusting immune system functions and inhibiting the viral fusion process with host cellular membranes. These extensive molecular components are predominantly found within the fruiting bodies and mycelium, and their antiviral effects stem from mechanisms involving augmented interferon production and the suppression of viral enzymes [142, 143].

As detailed in Table 3, endophytic fungi generate triterpenoids and various secondary metabolites. Specifically, marine-derived endophytic fungi, such as species of Aspergillus and Penicillium, are known producers of low-molecular-weight compounds like cordycepin (from Cordyceps militaris) and ergosterol derivatives. Cordycepin has demonstrated inhibition of the SARS-CoV-2 main protease (Mpro) and spike protein binding, exhibiting strong affinity in molecular docking investigations. Furthermore, compounds like jasmonic acid and putaminoxin D represent additional examples that effectively target viral proteases, possessing advantageous pharmacokinetic profiles. These metabolites, which are synthesized via fermentation processes, exert their effects by impeding viral morphogenesis, RNA replication, or entry into host cells [143, 144].

Artificial intelligence (AI) and machine learning for antimicrobial peptides discovery and design

Advances in computational tools have accelerated AMP identification from vast datasets, including microbiomes and proteomes, enabling de novo design of peptides with tailored properties (e.g., broad-spectrum activity, low toxicity). This addresses the challenge of screening thousands of natural AMPs manually [145].

To transcend the shortcomings of natural peptides, AI-powered methodologies apply generative models to fashion novel AMPs endowed with advantageous properties. Among the approaches utilized are genetic algorithms, Bayesian optimization, variational autoencoders (VAEs), generative adversarial networks (GANs), and diffusion models. ML plays a pivotal role in the rational design of human beta-defensins (hBDs), where it guides residue alterations to increase their positive charge and amphipathic character, leveraging predictive analytics from computational aids including Antimicrobial Peptide Scanner v2 and HAPPENN. Displaying comprehensive antibacterial properties against pathogens including Staphylococcus aureus and Pseudomonas aeruginosa, the custom-designed peptide IK-16-1 (IGKVLTRVKLLRRIK) proved to be non-cytotoxic and non-hemolytic, making it an effective component for cosmetic preservation in minute quantities [145–147].

Machine learning and deep learning models Machine learning (ML) and deep learning techniques have gained significant traction in biological sequence analysis. These methods involve converting protein sequences into machine-readable formats and encoding features for digital mapping using signal processing approaches. Various encoding strategies have been explored, such as the PC6 protein encoding method and pseudo amino acid composition (PseAAC). In addition, the influence of pre-trained models from natural language processing, such as Protrans and word2vec, is expanding into protein sequence analysis [145, 148].

Based on past research, dsAMP is an advanced AMP classification model markedly enhancing sequence prediction. It synthesizes previous protein classification models, uses a large-dataset protein pre-training model, and includes CNNs, attention, and bi-directional LSTMs. New studies indicate substantial progress in AMP sequence/function recognition accuracy, sensitivity, specificity. dsAMP effectively predicts AMPs via transfer learning on diverse bacterial data, even sparse, improving its broad use [146, 147].

To further advance AMP development, we introduce dsAMPGAN, a novel GAN-based AMP generation model. dsAMPGAN excels in generating AMPs with properties akin to the original peptides, including hydrophobicity, aromaticity, and net charge. As illustrated in Fig. 1, our comprehensive workflow highlights the unique contributions and advancements of dsAMP and dsAMPGAN. The combination of these two models can accelerate the discovery of novel AMPs and advance the development of antimicrobial drugs, especially in the face of the growing threat of drug resistance. This approach not only improves the accuracy of AMP design but also expands the application potential of AMPs, which is important in the context of antimicrobial resistance [19, 147].

Models like HydrAMP (a conditional variational autoencoder) generate peptides by learning continuous representations of sequences and antimicrobial properties. It disentangles structure from activity, allowing parameter-controlled creativity for unconstrained or analogue generation. In 2023–2025 studies, it produced peptides active against multidrug-resistant (MDR) strains with high validation rates [149–151].

LLM-Based approaches AMP-Designer uses large language models (LLMs) with prompt tuning to design AMPs in days. In 2025, it generated 18 broad-spectrum AMPs against Gram-negative bacteria in 11 days, with a 94.4% in vitro success rate; two candidates showed MICs as low as 2 µg/mL against Propionibacterium acnes and reduced bacterial loads in murine lung models without inducing resistance [19, 152].

Microbiome mining A 2024 machine learning approach analyzed 63,410 metagenomes and 87,920 prokaryotic genomes to create AMPSphere, a catalog of 863,498 non-redundant AMPs. Of 100 tested, 79 were active in vitro, with three (e.g., lachnospirin-1) reducing bacterial loads by 1,000-fold in mouse infection models, comparable to clinical antibiotics [147].

Conclusions

In conclusion, while viral infections and cancer remain significant public health challenges, the potential of AMPs offers a promising avenue for treatment. Despite their current limitations in clinical applications due to issues such as low stability and high cytotoxicity, advancements in modifying the structure and composition of AMPs present viable solutions. Techniques such as stabilization, hybridization, and conjugation can enhance the therapeutic efficacy of these compounds. Furthermore, combinational therapies involving AMPs alongside other drugs or nanotechnologies could revolutionize the treatment of drug-resistant diseases. As research progresses, clinical trials will be crucial in validating these innovative approaches and unlocking the full potential of AMPs in combating viral infections and cancer effectively. The future holds promise for these novel treatments to have a significantly positive impact on global health outcomes.

Due to their varied, selective, and multi-target properties, microbial and fungal metabolites are promising new anticancer treatments. These microbial/fungal AMPs offer versatile cancer therapy, drawing on natural origins for biocompatibility and multi-target effects. High selectivity for cancer cells, attributed to membrane distinctions, consistently results in lower chemotoxicity. Non-specific means and immune boosting address drug resistance, proving them efficacious in preclinical colorectal and breast cancers. A revolutionary advance, these AMPs drive precision oncology, adaptable for multimodal therapies.

Limited generalizability of DL models due to small sample sizes, and poor prediction of in vivo properties like toxicity and immunomodulation. Future directions include curating standardized datasets with in vivo validations, advancing LLMs and diffusion models for multi-property optimization, and community competitions for benchmarking.

Abbreviations

AMPs

Antimicrobial peptides

HDPs

Host defense peptides

LPS

Lipopolysaccharides

LEAP2

Liver-expressed antimicrobial peptide 2

GHSR

Growth hormone secretagogue receptor

ACPs

Anticancer peptides

HNP-1

Human neutrophil peptide 1

mTOR

Mechanistic target of rapamycin

ROS

Reactive oxygen species

TLR4

Toll-like receptor 4

LfcinB

Lactoferricin B

HNSCC

Head and neck squamous cell carcinoma

DSS

Dextran sulfate sodium

cyO4

Cycloviolacins O4

PI3K

Phosphatidylinositol 3-kinase

AKT

Protein kinase B

EGR-4

Growth response protein 4

MARK

Mitogen-activated protein kinase

FOXO1

Forkhead box o1

HSV

Herpes simplex virus

Bcl-2

B-cell lymphoma-2

ZIKV

Zika virus

HIV

Human immunodeficiency virus

WNV

West Nile virus

DENV

Dengue virus

VEEV

Venezuelan equine encephalitis virus

BMAPs

Bovine myeloid antimicrobial peptides

mCRAMPs

Mouse cathelicidin-related antimicrobial peptides

PRV

Pseudorabies virus

PEDV

Porcine epidemic diarrhea virus

TH

Tilapia hepcidin

NNV

Nervous necrosis virus

TGF-β1

Transforming growth factor beta-1

SP1

Specificity protein 1

NF

Nuclear factor

IFN

Interferon

Epi-1

Epinecidin-1

RGNNV

Red-spotted grouper nervous necrosis virus

SGIV

Singapore grouper iridovirus

CAMEL

Cecropin-melittin hybrid peptide

Author contributions

Author Contributions: Conceptualization and design, H.T. first draft, M.P. and A.B.; writing—original draft preparation, H.T.; writing—original draft preparation, software and design figures, H.T. and M.P.; data curation, writing—review and editing, H.T; supervision and project administration, H.T. All authors have read and agreed to the published version of the manuscript.

Funding

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This manuscript is a review and did not involve the collection or analysis of primary data from human participants or animals. Therefore, ethical approval was not required.

Consent for publication

Not applicable. This manuscript does not contain any individual person’s data in any form.

Competing interests

The authors declare no competing interests.