Thiazole-Based Peptides: History
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Peptides are distinctive biomacromolecules that demonstrate potential cytotoxicity and diversified bioactivities against a variety of microorganisms including bacteria, mycobacteria, and fungi via their unique mechanisms of action. Among broad-ranging pharmacologically active peptides, natural marine-originated thiazole-based oligopeptides possess peculiar structural features along with a wide spectrum of exceptional and potent bioproperties. Because of their complex nature and size divergence, thiazole-based peptides (TBPs) bestow a pivotal chemical platform in drug discovery processes to generate competent scaffolds for regulating allosteric binding sites and peptide–peptide interactions. The present study dissertates on the natural reservoirs and exclusive structural components of marine-originated TBPs, with a special focus on their most pertinent pharmacological profiles, which may impart vital resources for the development of novel peptide-based therapeutic agents.

  • azole-based peptide
  • marine sponge
  • peptide synthesis
  • thiazole
  • cytotoxicity
  • cyanobacteria
  • bioactivity

1. Introduction

Thiazole-based peptides (TBPs) are obtained from diverse resources, primarily from cyanobacteria, sponges, and tunicates. A thiazole ring can be part of a cyclic structure or connected in a linear chain of peptides either alone or with other heterocycles like oxazole (e.g., thiopeptide antibiotics), imidazole, and indole (in the forms of histidine and tryptophan), thiazoline, oxazoline, etc. Cyclic peptides have an advantage over their linear counterparts as cyclization offers a reduction in conformational freedom, resulting in higher receptor-binding affinities. Understanding the structure–activity relationship (SAR), different modes of action, and routes of synthesis as tools are of vital significance for the study of complex molecules like heterocyclic bioactive peptides, which have a broad spectrum of pharmacological activities associated with them. Further, the sudden increase in the number of peptide drug products is another good reason to study this particular category of compounds on a priority basis.

2. Resources

Various natural sources of TBPs and other heterocyclic rings containing cyclopolypeptides comprise cyanobacteria [8–40], ascidians [41–62], marine sponges [63–70], and sea slugs [71–73]. Moreover, actinomycetes, sea hare, red alga, and higher plants [74–80] were found to be other potential resources of TBPs.

3. Biological Activity

Although thiazole-containing cyclopolypeptides of marine origin are associated with a number of bioactivities including antitubercular, antibacterial, antifungal, and inhibitory activity against serine protease enzymes chymotrypsin and elastase; anti-HIV activity; antiproliferative activity; antimalarial activity; and inhibitory activity against the transcription factor activator protein-1, the majority of them were found to exhibit anticancer activity. Various pharmacological activity-associated marine-derived Tzl-containing cyclopolypeptides along with susceptible cell line/organism with minimum inhibitory concentration are tabulated in Table 1.

Table 1. Heterocyclic Tzl-based peptides (TBPs) with diverse pharmacological activities.

TBPs

Resource

Bioactivity

Susceptibilty

MICa Value

Haligramide A [63]

marine sponge

Haliclona nigra

Cytotoxicity against A-549 (lung),

HCT-15 (colon), SF-539 (CNSb), and SNB-19 (CNS) human tumor cell lines

5.17–15.62

μg/mL

Haligramide B [63]

marine sponge

Haliclona nigra

Cytotoxicity against A-549 (lung),

HCT-15 (colon), SF-539 (CNS), and SNB-19 (CNS) human tumor cells

3.89–8.82 μg/mL

Scleritodermin A [64]

marine sponge

Scleritoderma nodosum

Cytotoxicity against colon HCT116, ovarian A2780, and breast SKBR3 cell lines

0.67–1.9 μM

Obyanamide [12]

marine cyanobacterium

Lyngbya confervoides

Cytotoxicity against KBc and LoVo cells

0.58 and 3.14 µg/mL

Waiakeamide [66]

marine sponge

Ircinia dendroides

Anti-TB activity against Mycobacterium tuberculosis

7.8 μg/mL

Ulongamide A [13]

marine cyanobacterium

Lyngbya sp.

Cytotoxicity against KB and LoVo cells

1 and 5 µM

Guineamide B [14]

marine cyanobacterium

Lyngbya majuscula

Cytotoxicity against mouse neuroblastoma  cell line

15 µM

Calyxamide A [110]

marine sponge

Discodermia calyx

Cytotoxicity against P388 murine

leukemia cells

3.9 and 0.9 μM

Bistratamide J [50]

marine ascidian

Lissoclinum bistratum

Cytotoxic activity against the human colon tumor (HCT-116) cell line

1.0 µg/mL

Didmolamide A

and B [48]

marine tunicate

Didemnum molle

Cytotoxicity against several

cultured tumor cell lines (A549, HT29, and MEL28)

10–20 µg/mL

Aeruginazole A [91]

freshwater cyanobacterium

Microcystis sp.

Antibacterial activity againt

B. subtilis and S. albus

Cytotoxicity against MOLT-4 human leukemia cell line and peripheral blood lymphocytes

2.2 and 8.7 μM

 

 41 and 22.5 μM

Cyclotheonellazole A, B and C [68]

marine sponge

Theonella aff. swinhoei

Inhibitory activity against serine protease enzyme chymotrypsin

Inhibitory activity against serine protease enzyme elastase

0.62, 2.8, and

2.3 nM

0.034, 0.10, and 0.099 nM

Microcyclamide MZ602 [18]

cyanobacterium

Microcystis sp.

Inhibition activity of

chymotrypsin

75 μM

Dolastatin 3 [9]

marine cyanobacterium

Lyngbya majuscula

Inhibition of HIV-1 integrase (for the terminal-cleavage and strand-

transfer reactions)

5 mM

and 4.1 mM

Lyngbyabellin A [27]

marine cyanobacterium

Lyngbya majuscula

Cytotoxicity against KB cells (human nasopharyngeal carcinoma cell line) and LoVo cells (human colon adenocarcinoma cell line)

Cytotoxicity against HT29 colorectal adenocarcinoma and HeLa cervical carcinoma cells

Cytoskeletal-disrupting effects

 in A-10 cells

0.03 and 0.50 μg/mL

 

 

1.1 and 0.71 μM

 

0.01–5.0 μg/mL

Lyngbyabellin B [86]

marine cyanobacterium

Lyngbya majuscula

Toxicity to brine shrimp (Artemia salina)

Antifungal activity against Candida albicans (ATCC 14053) in a disk diffusion assay

Cytotoxicity against HT29 colorectal adenocarcinoma and HeLa cervical carcinoma cells

3.0 ppm

100 μg/disk

 

 

 

1.1 and 0.71 μM

Lyngbyabellin E [28]

 

marine cyanobacterium Lyngbya majuscula

Cytotoxicity against NCI-H460 human lung tumor and neuro-2a mouse neuroblastoma cells

Cytoskeletal-disrupting effects in A-10 cells

0.4 and 1.2 μM

 

 

0.01–6.0 μM

Lyngbyabellin H [28]

marine cyanobacterium

Lyngbya majuscula

Cytotoxicity against NCI-H460 human lung tumor and neuro-2a mouse neuroblastoma cells

0.2 and 1.4 μM

Lyngbyabellin N [29]

marine cyanobacterium

Moorea bouilloni

Cytotoxic activity against HCT116 colon cancer cell line

40.9 nM

27-Deoxy-

lyngbyabellin A [30]

marine cyanobacterium

Lyngbya bouillonii

Cytotoxicity against HT29 colorectal adenocarcinoma and HeLa cervical carcinoma cells

0.012 and 0.0073 μM

Lyngbyabellin J [30]

marine cyanobacterium

Lyngbya bouillonii

Cytotoxicity against HT29 colorectal adenocarcinoma and HeLa cervical carcinoma cells

0.054 and 0.041 μM

Raocyclamide A [32]

filamentous cyanobacterium

Oscillatoria raoi

Cytotoxicity against embryos of sea urchin Paracentrotus lividus

30 μg/mL (ED100)d

Tenuecyclamide A, C and D [105]

cultured cyanobacterium

Nostoc spongiaeforme

var. tenue

Cytotoxicity against embryos of sea urchin Paracentrotus lividus

10.8, 9.0, and 19.1 μM (ED100)

Dolastatin I [75]

sea hare

Dolabella auricularia

Cytotoxicity against HeLa S3 cells

12 μg/mL

Marthiapeptide A [74]

marine actinomycete

Marinactinospora thermotolerans SCSIO 00652

Antibacterial activities against Micrococcus luteus, Staphylococcus aureus, Bacillus subtilis, and Bacillus thuringiensis

Cytotoxicity against SF-268 (human glioblastoma) cell line, MCF-7 (human breast adenocarcinoma) cell line, NCI-H460 (human lung carcinoma) cell line, and HepG2 (human hepatocarcinoma) cancer cell line

2.0, 8.0, 4.0, and 2.0 μg/mL

 

 

 

0.38, 0.43, 0.47, and 0.52 μM

 

Keramamide G, H

and J [67]

marine sponge

Theonella sp.

Cytotoxicity against L1210 murine leukemia cells and KB human

epidermoid carcinoma cells

10 µg/mL

Keramamide K [109]

marine sponge

Theonella sp.

Cytotoxicity against L1210 murine leukemia cells and KB human

epidermoid carcinoma cells

0.72 and 0.42 µg/mL

Lissoclinamide 8 [55]

sea squirt

Lissoclinum patella

Cytotoxicity against T24 (bladder carcinoma cells), MRC5CV1 (fibroblasts), and lymphocytes

6, 1, and 8 μg/mL

Mechercharmycin A [79]

marine bacterium

Thermoactinomyces sp. YM3-251

Cytotoxic activity against A549 (human lung cancer) cells and Jurkat cells (human leukemia)

4.0 ´ 10−8 M and 4.6 ´ 10−8 M

Leucamide A [70]

marine sponge

Leucetta microraphis

Cytotoxicity against HM02, HepG2, and Huh7 tumor cell lines

5.2, 5.9, and 5.1 μg/mL

Bistratamide H [50]

marine ascidian

Lissoclinum bistratum

Cytotoxic activity against the human colon tumor (HCT-116) cell line

1.7 µg/mL

Patellamide E [58]

marine ascidian

Lissoclinum patella

Cytotoxicity against human colon tumor cells in vitro

 

125 µg/mL

Microcyclamide [35]

cultured cyanobacterium

Microcystis aeruginosa

Cytotoxicity against

P388 murine leukemia cells

1.2 µg/mL

Dolastatin E [76]

sea hare

Dolabella auricularia

Cytotoxicity against HeLa-S3 cells

22–40 μg/mL

Aerucyclamide A [38]

freshwater cyanobacterium

Microcystis aeruginosa PCC 7806

Antiparasite activity against Plasmodium falciparum K1 and Trypanosoma brucei rhodesiense

STIB 900

5.0 and 56.3 μM

Aerucyclamide B [38]

freshwater cyanobacterium

Microcystis aeruginosa PCC 7806

Antiparasite activity against Plasmodium falciparum K1 and Trypanosoma brucei rhodesiense

STIB 900

0.7 and 15.9 μM

Aerucyclamide C [38]

freshwater cyanobacterium

Microcystis aeruginosa PCC 7806

Antiparasite activity against Plasmodium falciparum K1 and Trypanosoma brucei rhodesiense STIB 900

2.3 and 9.2 μM

Aerucyclamide D [38]

freshwater cyanobacterium

Microcystis aeruginosa PCC 7806

Antiparasite activity against Plasmodium falciparum K1 and Trypanosoma brucei rhodesiense STIB 900

6.3 and 50.1 μM

Aerucyclamide A, B and C [37,38]

freshwater cyanobacterium

Microcystis aeruginosa PCC 7806

Grazer toxicity

against the freshwater crustacean Thamnocephalus platyurus

30.5, 33.8, and 70.5 μM

Aerucyclamide B and C [38]

freshwater cyanobacterium

Microcystis aeruginosa PCC 7806

Cytotoxic activity against Rat

Myoblast L6 cells

120 and 106 μM

Urukthapelstatin A [78]

marine-derived bacterium

Mechercharimyces asporophorigenens YM11-542

Cytotoxicity against A549 human lung cancer cells

12 nM

Mechercharmycin A [79]

marine-derived bacterium

Thermoactinomyces sp.

Cytotoxicity against A549 human lung cancer cells and Jurkat cells

4.0 ´ 10-8 M and 4.6 ´ 10-8 M

Ulithiacyclamide [56,117]

marine tunicate

Lissoclinum patella

Cytotoxic activity against L1210, MRC5CV1, T24, and CEM cell lines (continuous exposure)

0.35, 0.04, 0.10, and 0.01 μg/mL

Ulicyclamide [117]

marine tunicate

Lissoclinum patella

Cytotoxic activity against L1210 murine leukemia cells

7.2 μg/mL

Patellamide A [117]

marine tunicate

Lissoclinum patella

Cytotoxic activity against L1210 murine leukemia and human ALL cell line (CEM)

3.9 and 0.028 μg/mL

Patellamide B, C [117]

marine tunicate

Lissoclinum patella

Cytotoxic activity against L1210 murine leukemia cells

2.0 and 3.2 μg/mL

Venturamide A [34]

marine

cyanobacterium

Oscillatoria sp.

Antiparasitic activity against Plasmodium falciparum, Trypanasoma cruzi

Cytotoxicity against mammalian Vero cells and MCF-7 cancer cells

8.2 and 14.6 μM

 

86 and 13.1 μM

Venturamide B [34]

marine

cyanobacterium

Oscillatoria sp.

Antiparasitic activity against Plasmodium falciparum, Trypanasoma cruzi

Cytotoxicity against mammalian Vero cells

5.2 and 15.8 μM

 

56 μM

Bistratamides A and B [60]

aplousobranch

ascidian

Lissoclinum bistratum

Cytotoxicity against MRC5CV1 fibroblasts and T24 bladder carcinoma cells

50 and 100 µg/mL

Bistratamide M [61]

marine ascidian

Lissoclinum bistratum

Cytotoxicity against breast, colon, lung, and pancreas cell lines

18, 16, 9.1, and 9.8 μM

Balgacyclamide A [33]

freshwater cyanobacterium

Microcystis aeruguinosa EAWAG 251

Antimalarial activity against Plasmodium falciparum K1

9 and 59 μM

Balgacyclamide B [33]

freshwater cyanobacterium

Microcystis aeruguinosa EAWAG 251

Antiparasitic activity against Trypanosoma brucei

rhodesiense STIB 900

8.2 and 51 μM

a MIC—minimum inhibitory concentration, b CNS—central nervous system, c KB—ubiquitous KERATIN-forming tumor cell subline, d ED100—effective dose for 100% inhibition.

This entry is adapted from the peer-reviewed paper 10.3390/md18060329

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