Table 3.
A list of repurposing drugs (FDA approved, under-clinical trials and new hypothetical approaches) of the treatment options as anti-COVID-19; in view of the drugs main indication/the hypothetical repurposing indication as anti- COVID-19.
| Repurposing products | Main indication/Expected mechanism of action as anti SARS-CoV-2 (Repurposing indication) | Status in COVID-19 management | Refs |
|---|---|---|---|
| VEKLURY® (Remdesivir) |
An adenosine analog with antiviral activity. A hypothetical mechanism of antiviral action of remdesivir is its incorporation into the nascent RNA chain of the virus causing a prematurity for viral cycle termination; it is a post virus entry stage. | FDA approved | [43,44] |
| Aviptadil | A vasoactive intestinal polypeptide (VIP) administered to treat erectile dysfunction/ Block inflammatory cytokines. | FDA approved | [45,46] |
| Dexamethasone | A synthetic potent long-acting broad-spectrum corticosteroid for immune system disorders. Repurposing as anti-COVID-19 (Hypothesis): Potential anti-inflammatory containing the cytokine storm related to COVID-19. |
FDA approved | [[47], [48], [49]] |
| ACTEMRA® (Tocilizumab) KEVZARA® (Sarilumab) SYLVANT® (Siltuximab) |
-Interleukin-6 (IL-6) antagonists blocking the binding of IL-6 (a pro-inflammatory cytokine) to IL-6 receptors resulting in the suppressing of T cell activation, promoting of immunoglobulin secretion, initiation of hepatic acute-phase protein synthesis, and proliferation, differentiation, and stimulation of hematopoietic precursor cell. -Indicated for adults suffering from moderately to severely active rheumatoid arthritis (RA) with an inadequate response or intolerance to ≥1 disease-modifying antirheumatic drugs (DMARDs). Repurposing as anti-COVID-19 (Hypothesis):IL-6- receptor inhibitors; a key cytokine resulting to an inflammatory storm increasing alveolar-capillary blood-gas exchange dysfunction, especially impaired oxygen diffusion, and eventually cause pulmonary fibrosis and organ failure. It has a potential effect of an improvement of immune damaging, lung functional injuries and arterial oxygen saturation. |
Under clinical trials | [[50], [51], [52]] |
| Chloroquine Plaquenil® (Hydroxychloroquine) |
Strong Immunomodulant antimalarial agents with broad-spectrum antiviral activity. Hydroxychloroquine is a common drug in many autoimmune disorders; lupus and rheumatoid arthritis. Repurposing as anti COVID-19 (Hypothesis): Expected to act as anti-COVID-19 by: - Inhibiting pH-dependent viral fusion and replication. - Inhibiting viral assembly in endoplasmic reticulum-Golgi intermediate like structures. - Its immunomodulatory effect through cell signaling pathways and regulating the action of pro-inflammatory cytokines that can enhance its antiviral effect synergistically |
Under clinical trials | [[53], [54], [55]] |
| Corticosteroids and NSAIDs (Ibuprofen) |
Non-selective, reversible inhibition of the cyclooxygenase enzymes COX-1 and COX-2, for the treatment of rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA), juvenile idiopathic arthritis (JIA), pain and fever. Repurposing as anti-COVID-19 (Hypothesis): Used in the management of SARS/MERS-CoV outbreaks via Inhibiting the immune response and so the clearance of COVID-19 could be delayed. Corticosteroids have the disadvantage: - Increasing incidence of secondary bacterial and fungal infections. - Suppressing inflammatory response, highly responsive to the lung damage and acute respiratory distress syndrome (ARDS) during viral infection. |
Under clinical trials | [56,57] |
| DUPIXENT® (Dupilumab) | Fully human monoclonal antibody of an interleukin-4 receptor alpha-antagonist inhibiting IL-4 signaling via the Type I receptor; IL-4 and IL-13 signaling via the Type II receptor resulting in declined IL-4 and IL-13 cytokine-induced responses of the release of pro-inflammatory cytokines, chemokines, and IgE, indicated for the treatment of adult patients suffering from moderate-to-severe atopic dermatitis. Repurposing as anti-COVID-19 (Hypothesis): Via inhibiting IL-4 and IL-13, It is expected to reverse the following immunological reactions which result in lung impairment due to COVID-19: -CD4 + T and CD8 + T cells display a potential antiviral activity via balancing the reaction against SARS-CoV-2. CD4 + T cells induce the production of virus specific antibodies by promoting T-dependent B cells, while CD8 + T cells are cytotoxic killing cells infected by the virus. -Infection promotes T cells to differentiate in various subsets; T-helper1 (Th1), Th17, and subsequent massive release of pro-inflammatory cytokines; interleukin (IL)-1, IL-6, IL-8, IL‐21, TNFβ, and MCP1. The high production of these mediators due to viral persistence (cytokine storm) results inhibiting CD8 + T cells activation. |
Under clinical trials | [[58], [59], [60]] |
| Nafamostat-Mesilate and Gabexate-Mesilate |
A synthetic serine protease, used in trials studying the prevention of Liver Transplantation and Post-reperfusion Syndrome, and as an anticoagulant therapy for patients of continuous renal replacement therapy due to acute kidney injury Repurposing as anti-COVID-19 (Hypothesis): Blocking TMPRSS2-dependent host cell entry of SARS-CoV-2, where the SARS-CoV-2 spike protein (S) undergoes endocytosis into the viral envelope and mediates viral entry into cells; it depends on the cellular enzyme transmembrane protease serine 2 (TMPRSS2) cleaving and promote the S protein. SARS-CoV. Hence, TMPRSS2 is crucial for spread of SARS-CoV. |
Under clinical trials | [[61], [62], [63]] |
| KALETRA® (Lopinavir/Ritonavir) |
Protease Inhibitor; inhibitors of Gag-Pol polyprotein precursor's cleavage causing the formation of immature, noninfectious viral particles where ritonavir in combination with lopinavir act as a pharmacokinetic enhancer by inhibition of lopinavir inactivation metabolism, indicated as anti-HIV. Repurposing as anti-COVID-19: Expected to be anti-protease of SARS-CoV-2, via: Inhibition of the viral activity of 3CLpro, thereby suppressing the process of viral replication and release from host cells |
Under clinical trials | [[64], [65], [66]] |
| Ribavirin | - A nucleoside antihepaciviral agent (anti- hepatitis C virus); Antiviral action against RNA and DNA viruses; inhibition of inosine monophosphate dehydrogenase (IMPDH) cellular protein diminishing intracellular GTP which inhibits RNA replication of viral genomes, so viral growth might be disrupted. - Alternatively, its immunomodulatory effects are by suppression of IL-10. Inhibition of RNA polymerase activity and therefore inhibition of initiation and elongation RNA fragments are inhibited, so viral protein synthesis could be inhibited. |
Under clinical trials | [67,68] |
| Azithromycin | A macrolide antibiotic, indicated for community-acquired pneumonia, pharyngitis/tonsillitis/Expected to decrease the virus entry into cells. | Under clinical trials | [69] |
| Interferon alpha (IFN-α) |
Inhibitor of various stages of viral replication; viral entry, uncoating, mRNA synthesis and protein synthesis, used for hepatitis management. | Under clinical trials | [[70], [71], [72], [73]] |
| Teicoplanin | A glycopeptide antibiotic/Booster for the endosomal pH inhibiting low-pH viral cleavage of spike protein in endosome by Cathepsin L; it results that genomic RNA release and replication of viral life cycle are avoided. | Under clinical trials | [[74], [75], [76]] |
| Favipiravir | RNA-dependent RNA polymerase (RdRp) inhibitor. It displays antiviral effects against variant RNA viruses; Coronaviruses and Influenza viruses via being metabolized to an active form, favipiravir-RTP, as a substrate for viral RNA polymerases. Via binding of favipiravir to viral RNA polymerase, RNA polymerase activity would be inhibited. | Under clinical trials | [77,78] |
| Arbidol® (Umifenovir) |
A broad-spectrum antiviral effective agent against enveloped and non-enveloped RNA or DNA viruses; influenza virus type A and B, respiratory syncytial virus, SARS-CoV, adenovirus, HCV. Repurposing as anti-COVID-19 (Hypothesis): Expected to inhibit viral fusion with targeted membrane preventing the viral entrance to targeted cells. |
Under clinical trials | [[79], [80], [81]] |
| Vitamin C Ascorbic acid |
An antioxidant agent acting as a co-factor of many physiological reactions for immune augmentation; high dose intravenous (IV) vitamin C would be A potential agent in sepsis and septic shock management. Repurposing as anti-COVID-19 (Hypothesis): High dose vitamin C has dual effects; - A pro-oxidant agent for immune cells and as an antioxidant agent for lung epithelial cells. - Inhibition of lactate secretion from immune cells preserving the innate immunity of alveolar epithelial cells type II. |
Under clinical trials | [[82], [83], [84], [85]] |
| Ivermectin (Stromectol) |
A macrocyclic lactones (semi-synthetic derivative of avermectins) causing an influx of Cl- ions via the cell membrane of invertebrates by induction of specific ivermectin-sensitive ion channels; it results in hyperpolarization leads to muscle paralysis treating; nematode parasites, arthropod ectoparasite infestations such as scabies. Repurposing as anti-COVID-19 (Hypothesis): Suppressing the importin (IMP) α/β receptor; this is crucial for transmitting viral proteins into the host cell nucleus. |
Under clinical trials | [[86], [87], [88], [89]] |
| Kineret (Anakinra) |
Blockade of IL-1α and IL-1β act via IL-1 receptor 1 to induce the inflammatory cytokines and TNFα production; it results in the inflammatory cascade. The inflammasome is a complex of distinct proteins converting inactive prointerleukin-1β to active IL-1β, indicated for declining symptoms and delaying the progression of structural damage active rheumatoid arthritis (RA) Repurposing as anti-COVID-19 (Hypothesis): The SARS-CoV-2 causes epithelial damage resulting in the release of IL-1α; it recruits neutrophils and monocytes to the infectious site activating IL-1β in monocyte/macrophages. Additionally, the SARS-CoV-2 induces pro-IL-1β in monocyte/macrophages which induce consequently more IL-1 which recruits and induces further innate immune cells; This autoinflammatory loop, where IL-1α and IL-1β, can promote production and release of further IL-1 has to be regulated as an ongoing loop will induce and recruit furthr innate immune cells independent of the initially primary trigger. Anakinra blocks the IL-1 receptor (IL-1R). Hence, it prevents autoinflammation via blockade activity of IL-1α released from dead epithelial cells, and IL-1β produced by immune cells. IL-1-induced IL-6 will also be suppressed. The autoinflammatory loop can exacerbate from increase innate immune response into uncontrolled macrophage activation syndrome (MAS) a spectrum that associates with increasing ferritin levels. |
Under clinical trials | [[90], [91], [92], [93], [94]] |
| Jakafi® (Ruxolitinib) |
A selective monoclonal antibodies targeting IL-6 and suppressor of JAK1 and JAK2, for the treatment of myelofibrosis (MF), polycythemia vera, and steroid-refractory acute graft-versus-host disease (SR-aGVHD). Repurposing as anti-COVID-19 (Hypothesis): Via inhibitory activity on the cytokine storm associated with COVID-19 given that IL-6. |
Under clinical trials | [[95], [96], [97]] |
| Colchicine | Tubulin-Colchicine Complex; an inhibitor of mitosis and microtubule assembly bound to soluble, non-polymerized tubulin heterodimers to formulate a tubulin-colchicine complex. It interferes with microtubule formation and elongation, and colchicine induces microtubule de-polymerization, indicate for gouty arthritis. Repurposing as anti-COVID-19 (Hypothesis): Coronaviruses, members of the Nidovirales order, are enveloped; positive-sense, single-stranded RNA viruses, redirecting and readjusting host cell membranes for custom as part of the replication of viral genome and transcription; it moves in the cell in a pattern of correspondence to microtubule-associated transport, activating the formulation of double-membrane vesicles in infected cells. The infected cells by coronaviruses include the interaction of the cytoplasmic tail of the spike protein with cytoskeletal proteins; It results in viral entry. Additionally, microtubules are involved in the transport and assembly of spike proteins into virions during the replication cycle. The colchicine-tubulin complex may block viral entry and replication. |
Under clinical trials | [[98], [99], [100], [101], [102]] |
| Convalescent Plasma (FDA approved) | |||
| -Suppressing viremia by antibodies. -Antibody-dependent cellular cytotoxicity, complement activation and phagocytosis (ADCP). -Modification of inflammatory response, accomplished during the early response. -Suggestion: apart from the direct anti-viral properties, plasma components can provide other beneficial actions; restoring coagulation factors. |
[[103], [104], [105], [106], [107]] | ||
| Nano-bodies Therapy (Under clinical trials) Naturally arising single-domain antibody fragments isolated from camelid/ alpaca / llamas variable heavy-chain (VHH) antibodies; they display a uniqueness of biophysical properties of small size and thermo-stability, which permit nebulized administration (Fig. 6). | |||
| An alpaca nano-body | Isolated from an alpaca-derived single domain antibody fragment, Ty1; with specificities to receptor binding domain (RBD) of the SARS-CoV-2 spike, directly suppressing ACE2 engagement, bound to the RBD, obstructing ACE2; it binds to an epitope on the RBD accessible in both the ‘up’ and ‘down’ conformations, sterically lagging RBD-ACE2 binding. Ty1 neutralizes SARS-CoV-2 spike pseudo-virus as a 12.8 kDa nano-body. | [[108], [109], [110], [111]] | |
| MicroRNAs/ siRNA CRISPR/Cas13 |
Nucleic acid-based therapy MicroRNAs/CRISPR -Class of non-coding RNAs of RNAs 18 ∼ 25 nucleotides (nt) in length, with potential roles in post-transcriptional regulation of gene expression via complementary binding to the 3′-untranslated regions (3′-UTRs) of target gene mRNA to promote mRNA degradation and translational repression resulting in protein biosynthesis inhibition. -Clustered Regularly-Interspaced Short Palindromic Repeats (CRISPR) has adapted from the prokaryotic adaptive immune system CRISPR-associated (Cas) system, used as a novel and specific genome editing tool for other organisms. |
[[112], [113], [114], [115], [116]] | |
| Mechanism of action as anti-COVID-19 (Hypothesis), via: Host factors of cellular entry and trafficking of SARS-CoV-2 (Fig. 7A). Viral proteins crucial in survival and replication of SARS-CoV-2 (Fig. 7B). -ACE2 and TMPRSS2 are crucial receptors identified to facilitate the activation and binding of SARS-CoV-2, and its entry to the host cell; host miRNA 27b regulates ACE2 and viral miRNA 147–3p targets TMPRSS2, in case that therapeutic miRNAs can be delivered to the cells, binding of SARS-CoV-2 spike protein to these receptors can be suppressed. -Designing a synthetic miRNA complemented to 3′ translated region (3′ UTR) of Open Reading Frame (ORF-9) of SARS-CoV-2 at encoding a nucleocapsid phosphoprotein (N); it acts a key functional role both structural and non-structural roles in infection via forming the viral capsid and interacts with the viral membrane protein during assembly. Hence, it is hypothetical that targeting this gene may suppress the process of viral particle assembly. -Predictively, Six host miRNAs; let-7a, miR-101, miR-126, miR-23b, miR-378, and miR-98 act as anti-SARS-CoV-2 target genes of nonstructural protein (nsp), nucleocapsid and spike glycoprotein. -Via computational design of specific guide-RNA complementary to a sequence site of the viral RNA, CRISPR displays potentiality of Inhibition of viral function and replication via directly targeting and cleaving all viral positive-sense RNA of non-structural proteins (NSP1-NSP16), accessory proteins, and ORF1−10, and ORF1a/b (Fig. 7C). |
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