Marine Organisms as a Prolific Source of Bioactive Depsipeptides

Depsipeptides, an important group of polypeptides containing residues of hydroxy acids and amino acids linked together by amide and ester bonds, have potential applications in agriculture and medicine. A growing body of evidence demonstrates that marine organisms are prolific sources of depsipeptides, such as marine cyanobacteria, sponges, mollusks, microorganisms and algae. However, these substances have not yet been comprehensively summarized. In order to enrich our knowledge about marine depsipeptides, their biological sources and structural features, as well as bioactivities, are highlighted in this review after an extensive literature search and data analysis.


Introduction
Marine organisms are tremendously important sources of natural products since almost 40,000 compounds have been discovered and recorded in the MarinLit database (https:// marinlit.rsc.org/, accessed on 12 December 2022) [1]. Depsipeptides are an important group of polypeptides simultaneously containing ester and amide bonds, and they display a wide variety of biological properties [2,3]. A number of naturally occurring depsipeptides have been successfully developed as new drugs or are being evaluated in clinical trials, such as the antitumor agents romidepsin [4,5], plitidepsin (aplidine) [6,7], kahalalide F [8,9] and OBP-801 (spiruchostatin A) [10]. Generally, these substances are divided into two groups, namely, cyclic and non-cyclic, of which the former tends to display excellent bioactivity [11,12]. However, marine-derived depsipeptides have not yet been comprehensively summarized until now. In order to enrich our knowledge about these compounds, their origins and structural features, as well as their biological properties, are highlighted in this review.
According to an extensive literature search using the DNP (Dictionary of Natural Products) database as well as Web of Science and SciFinder tools, as many as 288 depsipeptides  have been isolated and characterized from marine organisms. As shown in Figure 1, the major producers of depsipeptides are marine cyanobacteria, which make up 55.90%, followed by marine sponges (18.06%), mollusks (10.41%), bacteria (7.99%), marine fungi (5.56%) and algae (2.08%). On the basis of biological sources and chemical structures, these marine depsipeptides are each introduced herein. Their detailed information is supplied in the Supplementary Materials.

Marine Cyanobacteria
Marine-cyanobacterium-derived depsipeptides  have diverse chemical structures and a wide variety of pharmacological activities, and most of them are cytotoxic [13]. Structurally, these metabolites are linear and cyclic depsipeptides containing

Marine Cyanobacteria
Marine-cyanobacterium-derived depsipeptides  have diverse chemical structures and a wide variety of pharmacological activities, and most of them are cytotoxic [13]. Structurally, these metabolites are linear and cyclic depsipeptides containing ɑ-amino or ɑ-hydroxy carboxylic acid residues, and the latter are the major components and can be further divided into five subgroups, including cyclic penta-, hexa-, and hepta-depsipeptides, thiazole-containing depsipeptides and others.
The key structural feature of tasiamide F (15) is the presence of a Phe-derived statine core, which contributes to its aspartic protease inhibitory activity [22]. Izenamides A, B and C (16)(17)(18) were purified from an Okinawan Lyngbya sp. and demonstrated an inhibitory effect on cathepsin D [23]. Grassystatins A-C (19)(20)(21) showed potency and selectivity against cathepsins D and E in vivo [24]. Maedamide (22) was reported as a novel chymotrypsin-inhibiting depsipeptide and strongly inhibited the growth of HeLa and HL60 cell lines [25]. Lyngbyabellins D (23) and P (24) are, respectively, produced by Lyngbya sp. and Okeania sp. and displayed strong antifouling and cytotoxic activities [26,27]. Gallinamide A (25) was presented as a new antimalarial pentapeptide from a Schizothrix sp. collected off the north coast of Panama [28]. Veraguamides K (26) and L (27) are two unique cytotoxic depsipeptides containing brominated alkynyls and were isolated from Oscillatoria margaritifera [29]. psipeptides (1-161) have diverse chemical struccal activities, and most of them are cytotoxic [13]. and cyclic depsipeptides containing ɑ-amino or the latter are the major components and can be uding cyclic penta-, hexa-, and hepta-depsipepand others.

Marine Cyanobacteria
Marine-cyanobacterium-derived depsipeptides (1-161) have diverse chemical structures and a wide variety of pharmacological activities, and most of them are cytotoxic [13]. Structurally, these metabolites are linear and cyclic depsipeptides containing ɑ-amino or ɑ-hydroxy carboxylic acid residues, and the latter are the major components and can be further divided into five subgroups, including cyclic penta-, hexa-, and hepta-depsipeptides, thiazole-containing depsipeptides and others.

Conclusions and Perspectives
In summary, as many as 288 depsipeptides have been discovered in marine organisms, including cyanobacteria, sponges, mollusks, bacteria, fungi and algae, among which marine cyanobacteria are the largest group of producers. Most of these substances are formed by closing the loops of their terminal amino acids. It is very exciting that a large number of marine-derived cyclodepsipeptides display potent cytotoxic effects since they have absolute advantages in structural rigidity, biochemical stability, binding affinity and membrane permeability, which greatly improve their anticancer activity [110], such as the hormones or hormone analogs oxytocin [111], octreotide [112] and vasopressin [113], the antibiotics vancomycin [114], daptomycin [115] and polymyxin B [116] and the immunosuppressant cyclosporine [117]. Therefore, the discovery of novel marine cyclodepsipeptides for new drug development has been attractive to academic researchers and pharmaceutical companies. In the past decade, however, the number of new marine depsipeptides has been greatly reduced, as almost all accessible marine organisms have been collected and chemically studied. Fortunately, marine microorganisms (such as Fusarium, Mciromonospora, Streptomyces) have been shown to be a rich and unexploited source of bioactive natural products due to vast species richness and the biosynthetic potential of secondary metabolites, especially those of symbiotic microbes in marine sponges, mollusks, tunicates, macroalgae and mangroves. Therefore, more efforts should be made toward strain separation and chemical research using classical methods (e.g., strain cultivation and fermentation, chromatographic and spectroscopic techniques) and advanced approaches (e.g., metabolomics, genome mining and engineering).

Conclusions and Perspectives
In summary, as many as 288 depsipeptides have been discovered in marine organisms, including cyanobacteria, sponges, mollusks, bacteria, fungi and algae, among which marine cyanobacteria are the largest group of producers. Most of these substances are formed by closing the loops of their terminal amino acids. It is very exciting that a large number of marine-derived cyclodepsipeptides display potent cytotoxic effects since they have absolute advantages in structural rigidity, biochemical stability, binding affinity and membrane permeability, which greatly improve their anticancer activity [110], such as the hormones or hormone analogs oxytocin [111], octreotide [112] and vasopressin [113], the antibiotics vancomycin [114], daptomycin [115] and polymyxin B [116] and the immunosuppressant cyclosporine [117]. Therefore, the discovery of novel marine cyclodepsipeptides for new drug development has been attractive to academic researchers and pharmaceutical companies. In the past decade, however, the number of new marine depsipeptides has been greatly reduced, as almost all accessible marine organisms have been collected and chemically studied. Fortunately, marine microorganisms (such as Fusarium, Mciromonospora, Streptomyces) have been shown to be a rich and unexploited source of bioactive natural products due to vast species richness and the biosynthetic potential of secondary metabolites, especially those of symbiotic microbes in marine sponges, mollusks, tunicates, macroalgae and mangroves. Therefore, more efforts should be made toward strain separation and chemical research using classical methods (e.g., strain cultivation and fermentation, chromatographic and spectroscopic techniques) and advanced approaches (e.g., metabolomics, genome mining and engineering).