Table 2. Nature-Derived Peptides Acting as GPCR Ligands.

Peptide name	Source	Targets	Mode-of-action	Peptide structure	Refs
BE-18257B	Bacteria (Streptomyces misakiensis)	EDNRA	Competitive antagonist	Cyclic pentapeptide	[74]
Duramycin	Bacteria (Streptomyces alboflavus)	CXCR3	Antagonist	19-Amino acid (aa) cyclic thiopeptide	[75]
RES-701-1, 701-2, 701-3, and 701-4	Bacteria (Streptomyces sp.)	EDNRB	Antagonist	16-aa cyclic peptides	[76]
SP 1, 2, 6-9	Bacteria (Streptococcus suis, Bacillus cereus, Psychromonas ingrahamii, Shewanella baltica, Desulfotomaculum reducens, and Borrelia burgdorferi)	FPR1, FPR2	Agonist	N-formylated signal hexapeptides	[77]
Brintonamides C, D, and Ea	Cyanobacteria (Oscillatoria sp.)	CXCR7, CCR10, OXTR, TACR2, SSTR3	Agonist, antagonist	Linear hexapeptides	[39]
CJ-15,208	Fungus (Ctenomyces serratus)	OPRK, OPRM, OPRD	Antagonist	Cyclic tetrapeptide	[78]
Cyclosporin-A and –H	Fungus (Tolypocladium inflatum)	FPR1	Antagonist	Cyclic undecapeptides	[79,80]
Endolide A and Bb	Fungus (Stachylidium sp.)	V1AR 5HT2B	n.d.	Cyclic N-methylated and 3-(3-furyl)-alanine-containing tetrapeptides	[38]
SCH-378161, –217048, –378199, and –378167	Fungus (taxonomically unidentified)	NK2R	Antagonist	Cyclic nonadepsipeptides	[81]
Rubiscolins 5 and 6	Plant (Spinacia oleracea)	OPRD	Agonist	Rubisco-derived linear penta-and hexapeptides	[82]
Kalata B7	Plant (Oldenlandia affinis)	OXTR, V1AR	Partial agonist	29-aa cyclic cystine-knot peptide; three disulfide bonds (I–IV, II–V, III–VI)	[17]
Caripe 8	Plant (Carapichea ipecacuanha)	CRFR1	Antagonist	31-aa cyclic cystine-knot peptide; three disulfide bonds (I–IV, II–V, III-VI)	[23]
Cyclopsychotride A	Plant (Psychotria longipes)	NTR1	Antagonist	31-aa cyclic cystine-knot peptide; three disulfide bonds (I–IV, II–V, III–VI)	[83]
Soymorphins 5, 6, and 7	Plant (Glycine max)	OPRM	Agonist	β-conglycinin-derived linear penta-, hexa-, and heptapeptides	[84]
Barettin and 8,9-dihydrobarettinc	Sponge (Geodia baretti)	5HT2A, 5HT2C, 5HT4R	n.d.	Brominated cyclodecapeptides	[85]
Polydiscamides B, C, and D	Sponge (Ircinia sp.)	SNSR	Agonist	13-aa depsipeptides	[86]
ρ-TIAd	Cone-snail (Conus tulipa)	ADRA1A; ADRA1B; ADRA1D	Competitive and non-competitive antagonist	C-terminally amidated 19-aa peptide; two disulfide bonds (I-III;II-IV)	[29,30]
Contulakin-G	Cone-snail (Conus geographus)	NTR1	Agonist	N-terminal pyroglutamate 16-aa O-linked glycopeptide	[87]
Conopressin T, S and Ge	Cone-snail (C. tulipa, Conus striatus, and C. geographus)	V1AR, OXTR, V1BR	Antagonist, partial agonist	C-terminally amidated nonapeptides; one disulfide bond	[88,89]
τ-CnVA and LiC32	Cone-snail (Conus consor and Conuslividus)	SSR3	Antagonist	C-terminally amidated 14- and 15-aa peptides; two disulfide bonds (I–III, II–IV)	[90]
Conorphin-T	Cone-snail (Conus textile)	OPRK	Agonist	C-terminally amidated nonapeptide; two disulfide bonds (I–II, III–IV)	[91]
BulA	Cone-snail (Conus bullatus)	LPAR6	Competitive antagonist	C-terminally amidated 13-aa peptide; two disulfide bonds (I–III,II–IV)	[92]
Vc1.1, RgIA, AuIB, Vc1.2, and PeIA	Cone-snail (Conus victoriae, Conus regius, Conus aulicus, and Conus pergrandis)	GABR1, GABR2	Allosteric modulator	C-terminally amidated 14- and 16-aa peptides; two disulfide bonds (I–III, II–IV)	[27]
Helokinestatin	Gila monster (Heloderma suspectum) and Mexican beaded lizard (Heloderma horridum)	BKRB2	Antagonist	Proline-rich decapeptide	[93]
Inotocinf	Black garden ant (Lasius nigert)	OXTR, V1AR, V1BR, and V2R	Agonist,allosteric modulator	C-terminally amidated nonapeptide	[71]
Apamin	Bee (Apis mellifera)	ACM2	Agonist	18-aa cyclic peptide; two disulfide bonds (I–III, II–IV)	[94]
THR6-BK	Wasp (Polybia occidentalis)	BKRB2	Agonist	Linear nonapeptide	[95]
NLP-24	Nematode (Caenorhabditis elegans)	OPRK, OPRM	Agonist	C-terminally amidated pentapeptide	[96]
α-Latrotoxin	Spider (Latrodectus tredecimguttatus)	ADGRL1	Agonist	128-kDa cysteine-rich polypeptide	[35]
δ-CNTX-Pn1a	Spider (Phoneutria nigriventer)	CNR1, OPRM, OPRD	Agonist	48-aa peptide; five disulfide bonds (I–V, II–III, IV–VI, VII–VIII, IX–	[36]
BmK-YA	Scorpion (Buthus martensii)	OPRM, OPRK, OPRD	Agonist	C-terminally amidated linear octapeptide	[37]
TsHpt-I	Scorpion (Titys serrulatus)	BKRB2	Agonist	25-aa linear proline-rich peptide	[97]
Bv8	Frog (Bombina variegata)	PKR1, PKR2	Agonist (Bombina variegata)	77-aa peptide; five disulfide bonds (I–V, II–III, IV–VI, VII–VIII, IX–X)	[89]
Kinestatin	Frog (Bombina maxima)	BKRB2	Antagonist	C-terminally amidated linear nonapeptide	[98]
Deltorphin-1 and –2 and dermorphin	Frog (Phyllomedusa sauvagii)	OPRM, OPRD	Agonist	C-terminally amidated linear heptapeptides	[99,100]
Mambaqauretin-1	Snake (Dendroaspis angusticeps)	V2R	Competitive antagonist	57-aa Kunitz-domain peptide;three disulfide bonds (I–VI, II–IV,III–V)	[34]
WTX	Snake (Naja kaouthia)	ACM1-ACM5	Allosteric modulator	66-aa peptide; five disulfide bonds (I–V, II–III, IV–VI, VII–VIII, IX–X)	[101]
γ-Bungarotoxin	Snake (Bungarus multicinctus)	ACM2	n.d.	68-aa peptide; five disulfide bonds (I–V, II–III, IV–VI, VII–VIII, IX–X)	[102]
ρ-Da1a and ρ-Da1bg	Snake (D. angusticeps)	ADRA1A, ADRA2A, DRD3	Non-competitive antagonist	66-aa peptides; four disulfide bonds (I–III, II–IV, V–VI, VII–VIII)	[103,104]
Sarafotoxins m, b and i3	Snake (Atractaspis irregularis)	EDNRB	Agonist	20-aa, 24-aa and 23-aa peptides; two disulfide bonds (I–IV, II–III)	[105]
β-Cardiotoxin	Snake (Ophiophagus hannah)	ADRB1, ADRB2	Antagonist	63-aa peptide; four disulfide bonds (I–III, II–IV, V–VI, VII–VIII)	[106]
α-Cobratoxin	Snake (Naja naja kaouthia)	ACM4	Agonist	71-aa peptide; five disulfide bonds (I–V, II–III, IV–VI, VII–VIII, IX–X)	[107]
MT-MIα	Snake (Micrurus lemniscatus)	ACM1–ACM5	Antagonist	Cysteine-rich peptide; 12-aa partial sequence available only	[108]
MT1 and MT2h	Snake (D. angusticeps)	ACM1, ACM4, ADRA2B	Agonist, antagonist, allosteric modulator	65 and 66-aa peptides, fourdisulfide bonds (I–III, II–IV, V–VI,VII–VIII)	[103,109]
MT3 (m-4 toxin) and MT6i	Snake (D. angusticeps)	ACM1, ACM4, ADRA1A, ADRA2A, ADRA2C	Antagonist, non-competitive antagonist	65-aa peptides, four disulfide bonds (I–III, II–IV, V–VI, VII–VIII)	[89,103]
MT4 and MT5j	Snake (D. angusticeps)	ACM1, ACM2, ACM4, ADRB2	Antagonist	65 and 66-aa peptides, four disulfide bonds (I–III, II–IV, V–VI,VII–VIII)	[89,110]
MT7 (m-1 toxin)	Snake (D. angusticeps)	ACM1	Negative allosteric modulator	65-aa peptide; four disulfide bonds (I–III, II–IV, V–VI, VII–VIII)	[103]
MT-α and MT-βk	Snake (Dendroaspis polylepis)	ACM1, ACM2, ACM3, ACM4, ACM5, ADRA2B	Antagonist	65 and 66-aa peptides, four disulfide bonds (I–III, II–IV, V–VI,VII–VIII)	[110,111]
Bj-PRO-7a	Snake (Bothrops jararaca)	ACM1	Agonist	Proline-rich linear heptapeptide	[112]
BM14	Snake (B. multicinctus)	ACM2	n.d.	82-aa peptide; five disulfide bonds (I–V, II–III, IV–VI, VII–VIII, IX–X)	[113]
Sarafotoxins a, c, and S6c	Snake (Atractaspis engaddensis)	EDNRA, EDNRB	Agonist	21-aa peptides; two disulfide bonds (I–IV, II–III)	[114,115]
Bibrotoxin	Snake (Atractaspis bibronii)	EDNRB	Agonist	21-aa peptide; two disulfide bonds (I–IV, II–III)	[116]
MIT1	Snake (D. polylepis)	PKR1, PKR2	Agonist	81-aa peptide; five disulfide bonds (I–V, II–III, IV–VI, VII–VIII, IX–X)	[89]
Crotalphine	Snake (Crotalus durissus terrificus)	OPRK	Agonist	14-aa peptide; one disulfide bond	[117]
MTLP-1	Snake (N. kaouthia)	ACM1–ACM5	n.d.	65-aa peptide; four disulfide bonds (I–III, II–IV, V–VI, VII–VIII)	[118]
Pep 1-8	Bovine	T2R4	Antagonist	Bovine protein-derived peptides	[119]
β-Lactotensin	Bovine	NTR2	Agonist	Bovine protein-derived peptide	[120]

GPCRs are listed using the protein name according to UniProt. For more details please refer to the IUPHAR/BPS Guide to Pharmacology. n.d. refers to not determined (ligand’s mode-of-action).

^aBrintoamides C, D, and E are agonists of CXCR7. Brintonamide C is further an antagonist of SSTR3 and TACR2. Brintonamide D antagonizes CCR10, OXTR, SSTR3, and TACR2. Brintonamide E acts as an antagonist of CCR10, OXTR, and TACR2.

^bEndolide A targets V1AR, while endolide B is selective for 5HT2BR.

^cBarettin binds to 5HT2A, 5HT2C, and 5HT4R, whereas 8,9-dihydrobarettin is selective for 5HT2C.

^dρ-TIA noncompetitively antagonizes ADRA1B, while it antagonizes ADRA1A and ADRA1D in a competitive manner.

^eConopressin S was shown to bind to V1AR, V1BR, and OXTR, while conopressin G was demonstrated to bind to OXTR. Their mechanism of action is not determined.

^fInotocin shows the ability to bind to human OXTR, V1AR, and V1BR but it acts as a full agonist on human V1BR, an allosteric modulator on human V₂R, and an antagonist on human V1AR.

^gρ-Da1a was reported to be a noncompetitive antagonist on ADRA1A whereas ρ-Da1b functions as an antagonist on ADRA2A and DRD3 in a noncompetitive manner.

^hThe mode-of-action of MT1 and MT2 is controversial. Several studies reported agonistic, antagonistic, competitive, or allosteric properties of these polypeptides. MT2 selectively binds to ACM1. Their mechanisms of action are summarized in [121].

ⁱVenom-derived MT3 shows affinity towards ACM4, ADRA1A, ADRA2A, and ADRA2C. It was reported as a highly potent and selective antagonist of ACM4. Synthetic form of MT3 was demonstrated to be a competitive antagonist of ACM4 as well as highly potent on α-adrenoceptors, in particular ADRA1A, ADRA2A, and ADRA2C. Herein, a noncompetitive antagonism was suggested. MT6 is proposed as an isotoxin of MT3 and its primary sequences have not been determined. It shows selectivity towards ACM1, but its mode-of-action is unknown.

^jMT4 was shown to be an antagonist of ACM1, ACM2, and ADRAB2. In contrast, MT5 binds to ACM1 and ACM4 but its mechanism of action is not known.

^kVenom-derived MT-α binds to muscarinic receptors; synthetic MT-α does not have muscarinic activity but rather antagonistic properties on ADRA2B. MT-β shows binding affinity towards ACM1, ACM3, and ACM4 but its detailed mode-of-action is unknown.