Marine natural product peptides with therapeutic potential: Chemistry, biosynthesis, and pharmacology

Abstract

The oceans are a uniquely rich source of bioactive metabolites, of which sponges have been shown to be among the most prolific producers of diverse bioactive secondary metabolites with valuable therapeutic potential. Much attention has been focused on marine bioactive peptides due to their novel chemistry and diverse biological properties. As summarized in this review, marine peptides are known to exhibit various biological activities such as antiviral, anti-proliferative, antioxidant, anti-coagulant, anti-hypertensive, anti-cancer, antidiabetic, antiobesity, and calcium-binding activities. This review focuses on the chemistry and biology of peptides isolated from sponges, bacteria, cyanobacteria, fungi, ascidians, and other marine sources. The role of marine invertebrate microbiomes in natural products biosynthesis is discussed in this review along with the biosynthesis of modified peptides from different marine sources. The status of peptides in various phases of clinical trials is presented, as well as the development of modified peptides including optimization of PK and bioavailability.

Keywords: Bioactive peptides; Biosynthesis; Challenges; Marine organisms; Peptide isolation; Therapeutic peptides.

Figure 1

Chemical structures of discodermins A-H and kasumigamide

Figure 2

Chemical structures of phakellistatins 1–12 and isophakellistatin 3

Figure 3

Chemical structures of phakellistatins 13–19

Figure 4

Chemical structures of geodiamolides A-R, geodiamolide-TA, neosiphoniamolide, jasplakinolide, and pipestelides A-C

Figure 5

Chemical structures of milnamides A-G, hemiasterlins A, D, and scleritodermin A

Figure 6

Chemical structures of mirabamides A-H

Figure 7

Chemical structures of celebesides A-C and theopapuamides A-D

Figure 8

Chemical structures of homophymines A-E and A1-E1

Figure 9

Chemical structures of neamphamides A-D

Figure 10

Chemical structures of callipeltins A-D

Figure 11

Chemical structures of callipeltins E-K

Figure 12

Chemical structures of callipeltins L-Q

Figure 13

Chemical structures of microspinosamide and carteritins A-B

Figure 14

Chemical structures of mycothiazole, dysidenin, isodysidenin, dysideaprolines A-F, barbaleucamides A-B, and dysithiazolamide

Figure 15

Chemical structures of microcionamides A-B

Figure 16

Chemical structures of halicylindramides A-C and seco-methyl ester of halicylindramide B

Figure 17

Chemical structures of haligramides A-B, waiakeamide, and sulfone derivative of waiakeamide

Figure 18

Chemical structures of corticiamide A, pembamide, cyclocinamides A-B, and kapakahines A-G

Figure 19

Chemical structures of taumycins A-B

Figure 20

Chemical structures of pipecolidepsins A-B

Figure 21

Chemical structures of halipeptins A-D

Figure 22

Chemical structures of tausalarin C, arenastatin A, and axinastatins 1–3

Figure 23

Chemical structures of hymenamides A-H and J-K

Figure 24

Chemical structures of wainunuamide, axinellins A-C, stylopeptides 1–2, stylostatins 1–2, and cyclonellin

Figure 25

Chemical structures of fenestins A-B and hymenistatin 1

Figure 26

Chemical structures of discobahamins A-B and calyxamides A-B

Figure 27

Chemical structures of microsclerodermins A-K and anhydromicrosclerodermin C

Figure 28

Chemical structures of aciculitins A-C and aciculitamides A-B

Figure 29

Chemical structures of polydiscamides A-D

Figure 30

Chemical structures of criamides A-B and gombamide A

Figure 31

Chemical structures of euryjanicins A-G and dominicin

Figure 32

Chemical structures of neopetrosiamides A-B, jamaicensamide A, sulfolipodiscamides A-C, and lipodiscamides A-C

Figure 33

Structures of stylissamides A-H, X, stylissatins A-D, and stylisins 1–2

Figure 34

Chemical structures of reniochalistatins A-E and yaku’amides A-B

Figure 35

Chemical structures of chujamides A-B and leucamide A

Figure 36

Chemical structures of azumamides A-E and phoriospongins A-B

Figure 37

Chemical structures of callyaerins A-H

Figure 38

Chemical structures of motuporin, theonellapeptolide Id, and nazumazoles A-F

Figure 39

Chemical structures of polytheonamides A-C

Figure 40

Chemical structures of pseudotheonamides A1-A2, B2, C-D, dihydrocyclotheonamide A, nazumamide A, cyclotheonamides A-B, and orbiculamide A

Figure 41

Chemical structures of cyclotheonamides E, E2, and E3

Figure 42

Chemical structures of theonellamides A-G, keramamides A-H, and J-N

Figure 43

Chemical structures of koshikamides A1-A2 and B-H

Figure 44

Chemical structures of papuamides A-F, theonegramide, nagahamide A, and cupolamide A

Figure 45

Chemical structures of barangamides A-D, theonellapeptolides Ia-Ie, and IId-IIe

Figure 46

Chemical structure of theonellapeptolide IIIe [169]

Figure 47

Chemical structures of congeners 1–2 and solomonamides A-B

Figure 48

Chemical structures of cyclolithistide A, revised structure of cyclolithistide A [176], theopalauamide A, isotheopalauamide, and oriamide

Figure 49

Chemical structures of miraziridine A, paltolides A-C, perthamides B-K, and mutremdamide A

Figure 50

Structural similarity of peptides isolated from Theonella sp., and microorganisms

Figure 51

Chemical structures of turnagainolides A-B, solonamides A-B, actinoramides A-C, fijimycins A-C, and brunsvicamides A-C

Figure 52

Chemical structures of malyngamides 2–3, cocosamides A-B, pitiprolamide, and pitipeptolides A-F

Figure 53

Chemical structures of lagunamides A-C, wewakamide A, and guineamides A-G

Figure 54

Chemical structures of wewakazole, wewakazole B, and wewakpeptins A-D

Figure 55

Chemical structures of porpoisamides A-B, bisebromoamide, and norbisebromoamide

Figure 56

Chemical structure of somocystinamide A

Figure 57

Chemical structures of cyclic desmethoxymajusculamide C, linear desmethoxymajusculamide C, majusculamides A-D, dolastatins 11–12, 57-normajusculamide C, lyngbyastatins 1, 3, epilyngbyastatin 1, and deoxymajusculamide D

Figure 58

Chemical structures of apratoxins A-E and dehydroapratoxin A

Figure 59

Chemical structures of dragonamides A-E, herbamides A-B, dragomabin, and carmabins A-B

Figure 60

Chemical structures of almiramides A-C

Figure 61

Chemical structures of grassystatins A-C

Figure 62

Chemical structures of lobocyclamides A-C and obyanamide

Figure 63

Chemical structures of hantupeptins A-C

Figure 64

Chemical structures of trungapeptins A-C and antanapeptins A-D

Figure 65

Chemical structures of palmyramide A, dudawalamides A-E, and mantillamide

Figure 66

Chemical structures of grassypeptolide and carriebowmide

Figure 67

Chemical structure of hoiamide A

Figure 68

Chemical structures of tiglicamides A-C, largamides A-C, and methyl esters of largamides A-C

Figure 69

Chemical structures of itralamides A-B

Figure 70

Chemical structures of lyngbyastatins 4–6 and 8–10

Figure 71

Chemical structures of somamides A-B, lyngbyastatin 7, kempopeptins A-B, and scyptolin A

Figure 72

Chemical structures of lyngbyazothrins A-D, pahayokolides A-B, schizotrin A, and tychonamides A-B

Figure 73

Chemical structures of grassypeptolides A-E and ibu-epidemethoxylyngbyastatin

Figure 74

Chemical structures of grassypeptolides F-G

Figure 75

Chemical structures of lyngbyapeptins A-D and lyngbyabellins A-J

Figure 76

Chemical structures of alotamide A, lyngbyabellins K-N, and 7-epi-lyngbyabellin L

Figure 77

Chemical structures of barbamide and jamaicamides A-C

Figure 78

Chemical structure of hectochlorin

Figure 79

Chemical structures of apramides A-G

Figure 80

Chemical structures of antillatoxin, barbaramide A, aurilide, aurilides B-C, and kalkitoxin

Figure 81

Chemical structures of georgamide and yanucamides A-B

Figure 82

Chemical structures of dysidenamide, pseudodysidenin, nordysidenin, and isodysidenin

Figure 83

Chemical structures of ulongamides A-F

Figure 84

Chemical structures of isomalyngamides A-B, malyngamides A-K, and 8-epi-malyngamide C

Figure 85

Chemical structures of malyngamides L-Y

Figure 86

Chemical structures of hermitamides A-B and laxaphycins A-B

Figure 87

Chemical structures of tasiamide, tasiamides B-F, pepstatin A, and tasipeptins A-B

Figure 88

Chemical structures of symplocamide A, symplocin A, veraguamides A-G, and semisynthetic veraguamide

Figure 89

Chemical structures of symplostatins 1–4

Figure 90

Chemical structures of malevamides A-D, belamide A, and largazole

Figure 91

Chemical structures of mitsoamide and gallinamide

Figure 92

Chemical structures of nostocyclamide, tenuecyclamides A-D, and cryptophycin

Figure 93

Chemical structures of microcystin, raocyclamides A-B, and venturamides A-B

Figure 94

Chemical structures of anabaenopeptins A-J and pompanopeptins A-B

Figure 95

Chemical structures of floridamide, coibamide A, scytonemin, hormothamnin A, and trichamide,

Figure 96

Chemical structures of arenamides A-C and caldoramide

Figure 97

Chemical structures of viequeamides A-F and companeramides A-B

Figure 98

Chemical structures of nodulapeptins A-B, aeruginosins NAL2, NOL6, spumigins A, C-H, and spumigins B1-B2

Figure 99

Chemical structures of kailuins A-H

Figure 100

Chemical structures of ngercheumicins A-I, unnarmicins A and C

Figure 101

Chemical structures of ariakemicins A-B, mollemycin A, thiocoraline, cyclomarins A-D, and cyclomarazines A-B

Figure 102

Chemical structures of surugamides A-F and champacyclin

Figure 103

Chemical structures of tumescenamides A-C and streptocidins A-D

Figure 104

Chemical structures of salinamides A-F

Figure 105

Chemical structures of tauramamide, tupuseleiamides A-B, and bogorols A-E

Figure 106

Chemical structures of loloatins A-D and marthiapeptide A

Figure 107

Chemical structures of loihichelins A-F, marinobactins A-C, D1, D2, and E

Figure 108

Chemical structures of aquachelins A-D, amphibactins B-I, petrobactin, petrobactin sulfate, aerobactin, and amphi-enterobactin

Figure 109

Chemical structures of alterobactins A-B and pseudoalterobactins A-B

Figure 110

Chemical structures of trivanchrobactin, divanchrobactin, vanchrobactin, anguibactin, and vibrioferrin

Figure 111

Chemical structures of ochrobactins A-C and synechobactins A-C

Figure 112

Chemical structures of unguisins A-F

Figure 113

Chemical structures of versicotides A-B, versicoloritides A-C, fellutamides A-D, F, and asperterrestide A

Figure 114

Chemical structures of sansalvamide A, scopularides A-B, and exumolides A-B

Figure 115

Chemical structures of cyclo-(L-Pro-L-Tyr), cyclo-(L-Pro-L-Val), cyclo-(L-Phe-L-Pro), and cis-bis(methylthio)silvatin

Figure 116

Chemical structures of penilumamide, penilumamides B-D, and asperpeptide A

Figure 117

Chemical structures of emericellamides A-B, guangomides A-B, homodestcardin, and azonazine

Figure 118

Chemical structures of endolides A-D and hirsutide

Figure 119

Chemical structures of simplicilliumtides A-H and dictyonamides A-B

Figure 120

Chemical structures of halolitoralins A-C, sclerotides A-B, cyclo(L-Pro-L-Val), cyclo(L-Pro-L-Leu), and cyclo(L-Ile-L-Val)

Figure 121

Chemical structures of RHM1, RHM2, and efrapeptin G

Figure 122

Chemical structures of cordyheptapeptides A-E and oryzamides A-E

Figure 123

Chemical structures of cycloxazoline, diazonamides A-E, revised structure of diazonamide A, and diazonamide A analog

Figure 124

Chemical structure of vitilevuamide

Figure 125

Chemical structures of bistratamides A-J, westiellamide, and didmolamides A-B

Figure 126

Chemical structures of lissoclinamides 1–8, patellamides A-E, ulithiacyclamide A, and ascidiacyclamide

Figure 127

Chemical structures of didemnins A-E, G-H, M-N, X-Y, epididemnin A1, nordidemnin N, and acyclodidemnin A

Figure 128

Chemical structures of eusynstyelamide and eudistomides A-B

Figure 129

Chemical structures of mollamide, mollamides B-C, keenamide A, and cycloforskamide

Figure 130

Chemical structures of virenamides A-C

Figure 131

Chemical structures of cyclodidemnamide, comoramides A-B, mayotamides AB, didmolamides A-B, prepatellamide A, patellamides A-C, and tamandarins A-B

Figure 132

Chemical structures of patellins 1–6 and trunkamide A

Figure 133

Chemical structures of kulolides 1–3, kulokainalide-1, kulomo’opunalides 1–2, and pupukeamide

Figure 134

Chemical structures of ulicyclamide, preulithiacyclamide, ulithiacyclamide, and ulithiacyclamide B

Figure 135

Chemical structures of nobilamides A-H, A-3302 A-B, and N-acetyl-L-phenylalanyl-L-leucinamide

Figure 136

Chemical structure of aplidine

Figure 137

Chemical structures of dolastatins 3, 10–15, homodolastatin 3, kororamide, and epidolastatin 12

Figure 138

Chemical structures of dolastatins 16–18 and homodolastatin 16

Figure 139

Chemical structures of dolastatins C-E, G-I, nordolastatin G, isodolastatin H, lyngbyastatin 2, and norlyngbyastatin 2

Figure 140

Chemical structures of dolabellin and doliculide

Figure 141

Chemical structures of kulokekahilides 1–2 and aurilide

Figure 142

Chemical structures of viridamides A-B, dolastatin 12, lyngbyastatin 1, malyngamide C, malyngamide C acetate, lyngbic acid, janadolide, and microcolins A-B

Figure 143

Chemical structures of tumonoic acids A-B, D-I, and epi-tumonoic acid

Figure 144

Chemical structures of onchidins A-B and nocardiamides A-B

Figure 145

Chemical structures of kahalalides A-H, J, W, norkahalalide A, isokahalalide F, and 5OH-kahalalide F

Figure 146

Chemical structures of kahalalides K, O-Q, R₁-R₂, S₁-S₂, V,X, and Y

Figure 147

Chemical structures of cis,cis-ceratospongamide, trans,trans-ceratospongamide, galaxamide, and mebamamides A-B

Figure 148

Chemical structures of echinocandin B, pneumocandins A₀, B₀, C₀, and caspofungin acetate

Figure 149

Biosynthesis of nodularin

Figure 150

Biosynthesis of barbamide & barbaleucamide

Figure 151

Biosynthesis of jamaicamide A

Figure 152

Biosynthesis of lyngbyatoxins [452]

Figure 153

Molecular networking of dolastatin 10 tetrapeptide molecular family

Figure 154

Biosynthesis of anabaenopeptins

Figure 155

Biosyntheses of aeruginosin and spumigin

Figure 156

Biosynthesis of thiocoraline

Figure 157

Biosynthesis of cyclomarin A and cyclomarazine A

Figure 158

Biosynthesis of surugamides

Figure 159

Biosynthesis of salinamides

Figure 160

Biosyntheses of amphibactins and marinobactins

Figure 161

Biosynthesis of amphi-enterobactin

Figure 162

Biosynthetic gene clusters of scopularide and emericellamide

Figure 163

Biosynthesis of Scopularide in Scopulariopsis brevicaulis

Figure 164

Biosynthesis of emericellamide in Aspergillus nidulans

Figure 165

Biosynthesis of N-methyl-3-(3-furyl)alanine

Figure 166

Biosynthesis of kasumigamide

Figure 167

Biosynthesis of polytheonamides

Figure 168

Biosynthesis of keramamides

Figure 169

Biosynthesis of microsclerodermins

Figure 170

Biosynthesis of patellamides

Figure 171

Chemical structure of ziconotide

Figure 172

Chemical structure of leconotide

Figure 173

Chemical structure of Xen-2174

Figure 174

Chemical structures of brentuximab vedotin and monomethylauristatin E

Figure 175

Chemical structures of soblidotin, tasidotin, and cemadotin

Figure 176

Chemical structure of elisidepsin

Figure 177

Chemical structure of HTI-286

Figure 178

Chemical structure of glembatumumab vedotin

Figure 179

Chemical structure of monomethylauristatin F