Skip to main content

REVIEW article

Front. Pharmacol., 25 October 2016
Sec. Experimental Pharmacology and Drug Discovery

The Pharmacological Potential of Non-ribosomal Peptides from Marine Sponge and Tunicates

  • TERI–Deakin Nano Biotechnology Centre, The Energy and Resources Institute, New Delhi, India

Marine biodiversity is recognized by a wide and unique array of fascinating structures. The complex associations of marine microorganisms, especially with sponges, bryozoans, and tunicates, make it extremely difficult to define the biosynthetic source of marine natural products or to deduce their ecological significance. Marine sponges and tunicates are important source of novel compounds for drug discovery and development. Majority of these compounds are nitrogen containing and belong to non-ribosomal peptide (NRPs) or mixed polyketide–NRP natural products. Several of these peptides are currently under trial for developing new drugs against various disease areas, including inflammatory, cancer, neurodegenerative disorders, and infectious disease. This review features pharmacologically active NRPs from marine sponge and tunicates based on their biological activities.

Introduction

Nature provides a wide and structurally diverse array of active biomolecules that have proved vital for the development of novel pharmaceuticals. The marine world, covering more than 70% of the Earth's surface, is the home of tremendous biodiversity. Due to very diverse oceanic environments, marine organisms have developed the capacity to produce unique compounds (Steele, 1985; Mehbub et al., 2014). This rich and unprecedented chemo diversity of marine natural products provides an unlimited resource of novel biomolecules in the field of drug development. The importance of marine metabolites in current drug research is driven by the fact, that during 1981–2002, around half of US FDA-approved drugs consisted of either marine metabolites or their synthetic analogs (Vinothkumar and Parameswaran, 2013). Interestingly, the majority of these natural products involved in clinical or preclinical trials are produced by invertebrates, that is, sponges, tunicates, bryozoans, or molluscs. Sixty per cent of these natural products belong to non-ribosomal peptide (NRP) families, which are biosynthesized by poly-functional mega-synthases called NRP synthetases (NRPSs) (Finking and Marahiel, 2004; Mehbub et al., 2014). The excellent binding properties, low off-target toxicity, and high stability of NRPs make them a promising molecule for development of new therapeutics. Currently, only a handful of NRPs are used as drug (Table 1).

TABLE 1
www.frontiersin.org

Table 1. NRPs-based drugs in market.

Marine sponges (Phylum porifera) represent the most primitive multicellular animals, with origins dating back to the Precambrian era (Hentschel et al., 2002). There are about 9000 reported species of sponges and (perhaps twice as many unreported species) available in the ocean (Brusca et al., 1990; Wörheide et al., 2005). These have been broadly categorized in 3 classes : Calcarea (5 orders and 24 families), Demospongiae (15 orders and 92 families), and Hexactinellida (6 orders and 20 families). Till date, more than 5300 different natural products have been isolated from marine sponges, and each year more than 200 additional new metabolites are being discovered (Laport et al., 2009; Mehbub et al., 2014). There are several sponge derived metabolites currently available in market and many in clinical studies (Table 2).

TABLE 2
www.frontiersin.org

Table 2. Sponge secondary metabolites that are FDA-approved agents in clinical trial (Mayer et al., 2010; Newman and Cragg, 2016).

It is proposed that some of the bioactive compounds isolated from sponges are produced by functional enzyme clusters originated from the sponges and their associated microorganisms (Laport et al., 2009; Thomas et al., 2010). It has been observed that bacterial phyla such as Proteobacteria, Nitrospira, Cyanobacteria, Bacteriodetes, Actinobacteria, Chloroflexi, Planctomycetes, Acidobacteria, Poribacteria, and Verrucomicrobia besides members of the domain Archaea are most sponge-associated bacterial community (Hentschel et al., 2002; Olson and McCarthy, 2005). However, fungi and microalgae also symbiotically inhabit sponges. It has been recognized that one host sponge can possess diverse symbionts. For example, unicellular heterotrophic bacteria, unicellular cyanobacteria, and filamentous heterotrophic bacteria all grow together in sponge Theonella swinhoei (Bewley et al., 1996). Likewise, a sponge belonging to Aplysina includes heterogeneous bacteria Bacillus sp., Micrococcus sp., Arthrobacter sp., Vibrio sp., Pseudoalteromonas sp., and so on (Hentschel et al., 2001). Sponge Rhopaloeides odorabile has β-Proteobacteria, γ-Proteobacteria, Cytophaga, Actinobacteria, and green sulfur bacteria (Webster et al., 2001). Besides this, species-specific symbiotic relationship has also been observed. For example, sponge T. swinhoei and δ-proteobacteria have shown a specific association with each other (Schmidt et al., 2000). A species of α-proteobacteria dominates in sponge R. odorabile over various habitats but is not detected from seawater, which strongly suggests that the symbiont is species specific (Lee Y. K. et al., 2001). On the other hand, one symbiont occurs commonly in various sponges from different regions indicating its wide host range (Wilkinson et al., 1981). For example, cyanobacteria Aphanocapsa sp., Phormidium sp., or Oscillatoria spongeliae are found in numerous sponges (Wilkinson, 1978). Symbiotic associations between sponges and marine microorganisms might be involved in nutrient acquisition, stabilization of sponge skeleton, processing of metabolic waste, and secondary metabolite synthesis. It is assumed that symbiotic marine microorganisms harbored by sponges are the original producers of some of these bioactive compounds (Newman and Hill, 2006). For example, antibiotic polybrominated biphenyl ether isolated from the sponge Dysidea herbacea (Demospongiae) are actually produced by endosymbiotic cyanobacterium O. spongeliae (Unson et al., 1994). A symbiotic bacterium Micrococcus sp. produces diketopiperazines previously ascribed to the host sponge Tedania ignis (Stierle et al., 1988). Another symbiotic bacterium Vibrio sp. produces brominated biphenyl ethers formerly attributed to the host sponge Dysidea sp. (Elyakov et al., 1991). Symbiotic bacterium Vibrio sp. produces an anti-Bacillus peptide andrimid that was found in the sponge Hyatella sp. extract (Oclarit et al., 1994). Antimicrobial activity is detected in Micrococcus luteus isolated from the sponge Xestospongia sp. (Bultel-Poncé et al., 1998). Antimicrobial compounds such as quinolones and phosphatidyl glyceride are isolated from a Pseudomonas sp. collected at the surface of the sponge Homophymia sp. (Bultel-Poncé et al., 1999). However, the mutual mechanism between sponge and its microbial associate, in metabolite production, is not well-understood. Thus, it is extremely relevant to highlight the therapeutic potential of various secondary metabolites synthesized by the microbial flora inhabiting sponges. This is because they open up the possibility of providing a continuous supply of the biologically active compounds by laboratory cultivation of the producer (Thomas et al., 2010).

Tunicates include a wide variety of invertebrates that are classified within the Phylum chordata based on presence of a larval notochord during early development. Tunicates contains about 2150 described species that are divided into 4 classes: Ascidiacea (Aplousoobranchia, Phlebobranchia, Stolidobranchia) Thaliacea (Pyrosomida, Doliolida, Salpida), Appendicularia (Larvacea), and Sorberacea (Ruppert and Fox, 2004). Amongst these, Ascidacea (commonly known as the ascidians) are highly studied due to their biologically active metabolites that serve as antineoplastic agents. Geranyl hydroquinone was first ascidian metabolite isolated from Aplidium sp. which displayed chemo protective activity against some forms of leukemia, rous sarcoma, and mammary carcinoma in test animals (Fenical, 1976) (Menna, 2009). Since then, ascidians are known as the source of numerous marine natural products. The biologically active metabolites originated from tunicates which are approved by FDA or in clinical trials along with their biological properties are given in Table 3.

TABLE 3
www.frontiersin.org

Table 3. Tunicate secondary metabolites that are FDA-approved agents or in clinical trial (Mayer et al., 2010; Newman and Cragg, 2016).

To date, significant biological activities, such as antimicrobial, anticancer, neurotoxic, antiprotozoal and their associated cellular targets have been reported for several NRPs from the marine sponges and tunicates. These NRPs have unique structures as compared with those from other sources. It is this attribute that makes marine sponge- and tunicate-derived NRPs highly attractive as potential drug and molecular probes. In this review, we survey the discoveries of NRPs derived from marine sponges and tunicates, which have shown in vivo efficacy or potent in vitro activity against various human diseases. Our objective is to highlight NRPs that have the greatest potential to be clinically useful. The details of sponge- and tunicate-derived NRPs along with biological properties is given Table 4.

TABLE 4
www.frontiersin.org

Table 4. Biological activities of NRPs isolated from marine sponges and tunicates.

Anticancer NRPs from Marine Sponges and Tunicates (Figures 16)

Sponge Theonella aff. mirabilis was the source of linear penta peptide Miraziridine A (1), which showed inhibitory activity on cathepsin B with an IC50 value of 1.4 μg/mL (Nakao et al., 2000). Two cyclic hexapeptides, Haligramides A (2) and B (3), were isolated from an aqueous extract of the sponge H. nigra. Both compounds exhibited cytotoxicity against various cell lines. Haligramide A exhibited cytotoxicity against A-549, HCT-15, SF-539, SNB-19 cell line with IC50 values of 5.17, 15.62, 9.00, and 9.08 μg/mL, respectively. Haligramide B, was found to be more active than Haligramide A against A-549, HCT-15, SF-539, SNB-19 cell line with IC50 values of 3.89, 8.82, 5.01, and 6.56 μg/mL, respectively (Rashid et al., 2000).

FIGURE 1
www.frontiersin.org

Figure 1. Structures of anticancer non-ribosomal peptides (1–14).

FIGURE 2
www.frontiersin.org

Figure 2. Structures of anticancer non-ribosomal peptides (15–26).

FIGURE 3
www.frontiersin.org

Figure 3. Structures of anticancer non-ribosomal peptides (27–33).

FIGURE 4
www.frontiersin.org

Figure 4. Structures of anticancer non-ribosomal peptides (34–42).

FIGURE 5
www.frontiersin.org

Figure 5. Structures of anticancer non-ribosomal peptides (43–60).

FIGURE 6
www.frontiersin.org

Figure 6. Structures of anticancer non-ribosomal peptides (61–69).

A cyclic peptide, Prepatellamide A (4) was isolated from the cytotoxic extracts of L. patella. The crude extract of this ascidian showed cytotoxicity against P388 murine leukemia cell lines with IC50 = ~5 μg/mL (Fu et al., 2000). Naturally occurring depsipeptides, Tamandarins A and B (5 and 6) were discovered from a Brazilian ascidian of the family Didemnidae and were cytotoxic against various human cancer cell lines including pancreatic carcinoma BX-PC3, IC50 = 1.79, 2.00 μg/mL, prostatic cancer DU-145, IC50 = 1.36, 1.53 μg /mL, head and neck carcinoma UMSCC10b, IC50 = 0.99, 1.7 6 μg/mL, respectively (Vervoort et al., 2000). Microscleroderma sp. from Palau gave 4 new cyclic peptides, Microsclerodermins F–I (7–10), all of which inhibited the growth of C. albicans with MIC value of 1.5, 3, 12, and 25 μg per disk, respectively, and also showed cytotoxicity against the HCT-116 cell line with IC50 value of 1.8, 2.4, 1.0, and 1.1 μg/mL, respectively (Qureshi et al., 2000).

A histidine-containing proline-rich cyclic heptapeptide, Wainunuamide (11), was isolated from the Fijian marine sponge S. aurantium. Compound (11) exhibited weak cytotoxic activity against A2780 ovarian tumor and K562 leukemia cancer cells with ID50 of 19.15 and 18.36 μg/mL, respectively (Tabudravu et al., 2001). The Australian marine sponge L. microraphis was the source of a bioactive cyclic heptapeptide, Leucamide A (12). Compound (12) inhibited the growth of the 3 tumor cell lines HM02 (gastric, GI50 = 5.2 μg/mL), HepG2 (liver, GI50 = 5.9 μg/mL), and Huh7 (liver, GI50 = 5.1 μg/mL) (Kehraus et al., 2002). The Fijian collection of marine sponge S. aurantium gave a proline-rich cyclic octapeptide, Axinellin C (13) (cyclo [Thr1-Val2-Pro3-Trp4-Pro5-Phe6-Pro7-Leu8]). Axinellin C displayed weak cytotoxicity against A2780 ovarian tumor and K562 leukemia cancer cells with ID50s of 13.17 and 4.46 mg/mL, respectively (Tabudravu et al., 2002). The crude extract of a marine sponge Cymbastela sp. (Papua New Guinea) gave a cytotoxic peptide Milnamide D (14). Milnamide D was found to exhibit cytotoxicity against HCT-116 at IC50 value of 66 nM and inhibition of tubulin polymerization at IC50 of 16 μM (Chevallier et al., 2003).

Investigation of marine sponge C. olemda yielded 3 new Kapakahines E−G (15–17). Only kapakahines E was found to display moderate cytotoxicity against P388 murine leukemia cells at IC50 of 5.0 μg/mL (Nakao et al., 2003). Two novel cyclic hexapeptides, Didmolamides A-B (18 and 19) were isolated from ascidian D. molle (Madagascar). Both peptides showed mild cytotoxicity against tumor cell lines (Lung—A549, Colon—HT29, and Skin—MEL28) with IC50 values of 10–20 μg/mL (Rudi et al., 2003). The Philippines ascidian L. bistratum was the source of 6 cyclic hexapeptides, Bistratamides E-J (20–25) which showed weak to moderate activity against the human colon tumor (HCT-116) cell line (IC50's: 3, 7.9; 4, 28; 5, 5; 6, 1.7; 7, 9; 8, 1 μg/mL, respectively) (Perez and Faulkner, 2003). Milnamide C (26) was isolated from Auletta sp., which showed significant activity against MDA-MB-435 breast cancer cells with IC50 values of 3.2 × 10−1 μg/mL (Sonnenschein et al., 2004).

Scleritodermin A (27), a new cyclic peptide, was isolated from the Lithistid Sponge S. nodosum. Scleritodermin A, inhibited tubulin polymerization and demonstrated significant in vitro cytotoxicity against a panel of human tumor cell lines (IC50 < 2 μM), including colon (HCT116), ovarian (A2780), and breast carcinoma cell lines SKBR3 (Schmidt et al., 2004). Microcionamides A (28) and B (29) were isolated from the Philippine marine sponge Clathria (Thalysias) abietina. Both compounds displayed significant cytotoxicity toward human breast tumor cell lines MCF-7 and SKBR-3 with IC50 of 125 and 98 nM for compound (28) and 177 and 172 nM for compound (29), respectively (Davis et al., 2004). Methanol extract of an Indonesian marine sponge Haliclona sp. gave a linear peptide Kendarimide A (30) which reversed P-glycoprotein-mediated multi-drug resistance in mammalian cells (Aoki et al., 2004).

Cycloheptapeptide, Phakellistatin 14 (31), was isolated from Phakellia sp., (Chuuk, Federated States of Micronesia). Compound (31) exhibited cytotoxicity against the murine lymphocytic leukemia P388 cell line at ED50 of 5 μg/mL (Pettit and Tan, 2005). The marine sponge T. swinhoei was found to produce highly cytotoxic polypeptides Polytheonamides A and B (32–33) with 48 amino acid residues. Both compounds were found to be cytotoxic against P388 murine leukemia cells with IC50 values of 78, 68 pg/mL, respectively (Hamada et al., 2005). Two diastereomeric tricyclic peptides Neopetrosiamdes A (34) and B (35) have been isolated from the marine sponge Neopetrosia sp. collected in Papua New Guinea. These peptides inhibited amoeboid invasion of human tumor cells at 6 μg/mL (Williams et al., 2005). Six new depsipeptides, Seragamides A–F (36–41) were isolated from sponge S. japonicas (Okinawan). Except seragamide F, all seragamides have showed multinuclei formation in NBT-T2 cells at 0.01, 0.02, 0.01, 0.01, and 0.04 mg/mL, respectively. Compound (36) also promotes the polymerization of G-actin and stabilizes F-actin filaments (Tanaka et al., 2006). Theonella swinhoei from Papua New Guinea gave a cyclic depsipeptide, Theopapuamide (42). This peptide contains several unusual amino acid residues such as β-methoxyasparagine, 4-amino-5-methyl-2, 3, 5-trihydroxy-hexanoic acid, and also contains an amide linked fatty acid moiety, 3-hydroxy-2, 4, 6-trimethyl-octanoic acid (Htoa) with cytotoxicity against CEM-TART (EC50 = 0.5 μM) and HCT-116 (EC50 = 0.9 μM) cell lines (Ratnayake et al., 2006).

Azumamide A-E (43–47) carboxylic acid containing histone deacetylase (HDAC) inhibitor cyclotetrapeptides were recovered from the sponge M. izuensis. Only compound (47) displayed human histone deacetylase inhibitory activity (Maulucci et al., 2007). An Indonesian sponge C. aerizusa gave a new cyclic peptide named Callyaerin G (48) with cytotoxicity against mouse lymphoma cell line (L5178Y) and HeLa cells with ED50(s) of 0.53 and 5.4 ug/mL, respectively (Ibrahim et al., 2008). The Papua New Guinea marine sponge Stylotella sp. was found to produce a new proline-rich cyclodecapeptide, Stylopeptide 2 (49) which inhibited the growth of BT-549 and HS 578T 2 breast cancer cell lines by 77 and 56%, respectively (Brennan et al., 2008). Bioactive lipopeptides Ciliatamides A-C (50–52) were isolated from the deep-sea sponge A. ciliate. Ciliatamides A-B have showed anti-leishmanial activity at 10 μg/mL with 50 and 45.5% growth inhibition, respectively. Ciliatamides A-C also inhibited growth of HeLa cells with IC50 values of 50, 4.5, and 50 μg/mL, respectively (Nakao et al., 2008).

The marine ascidian Diazona sp. (Indonesia) gave 3 new macrocyclic peptides, Diazonamides C–E (53–55). All the isolated peptides displayed moderate cytotoxicity against a panel of 3 human tumor cell lines (IC50's: A549 = 2.2, 2.9, 8.0 μg/mL; HT29 = 1.8, 2.9, 5.2 μg/mL; MDA-MB-231 = 2.2, 3.1, 9.0 μg/mL) (Fernández et al., 2008). Dominican marine sponge E. laughlini gave 2 cyclic heptapeptides, Rolloamides A (56) and B (57). Rolloamide A displayed significant growth suppression against several cancer cells (prostate, breast, ovarian, glioma, and renal) with IC50's of 0.4–5.8 μM (Williams et al., 2009). Proline-containing cycloheptapeptide, Euryjanicin A (58) was extracted from the marine sponge P. laughlini (Vicente et al., 2009). Bioassay guided extraction of the sponge C. aerizusa (Ambon, Indonesia) revealed 7 new cytotoxic cyclic peptides Callyaerins A–F (59–64) and H (65). All peptides have showed cytotoxicity, however, callyaerins E and H exhibited strong activity against the L5178Y lymphoma cell line with ED50 values of 0.39 and 0.48 μM, respectively (Ibrahim et al., 2010).

An undescribed sponge of the genus Melophlus sp. (Karumolum, Russell Is., Solomon Is.) yielded 2 depsipeptides, Papuamides E (66) and F (67), which were cytotoxic against brine shrimp with LD50 values between 92 and 106 μg/mL (Prasad et al., 2011). A proline-rich octapeptide Stylissamide X (68) isolated from an Indonesian marine sponge of Stylissa sp. inhibited HeLa cells in the concentration range 0.1–10 μM through wound-healing assay (Arai et al., 2012). The marine sponge C. gombawuiensis collected from Korean waters gave a disulphide-linked hexapeptide, Gombamide A (69). Gombamide A showed weak cytotoxic activity against the K562 and A549 cell lines with LC50 values of 6.9 and 7.1 μM, respectively, as well as moderate inhibitory activity against Na+/K+-ATPase with an LC50 value of 17.8 μM (Woo et al., 2013).

Anti-HIV Agents (Figures 7, 8)

The marine sponge S. microspinosa was the source of a cyclic depsipeptide Microspinosamide (70), inhibited HIV-1 infection with an EC50 value of approximately 0.2 μg/mL (Rashid et al., 2001). A Papua New Guinea collection of the marine sponge N. huxleyi has been shown to produce a new HIV-inhibitory cyclic depsipeptide, Neamphamide A (71). Neamphamide A displayed potent cytoprotective activity against HIV-1 infection with EC50 value ~28 nM (Oku et al., 2004). Four cyclic depsipeptides, Mirabamides A–D (72–75), were isolated from the marine sponge S. mirabilis. Mirabamides A, C and D inhibited HIV-1 fusion (Mirabamides A IC50 values between 40 and 140 nM: Mirabamides C IC50 values between 140 nM and 1.3 μM: and Mirabamides D IC50 values between 190 nM and 3.9 μM). Mirabamides A–C also inhibited the growth of B. subtilis and C. albicans at 1–5 μg/disk (Plaza et al., 2007).

FIGURE 7
www.frontiersin.org

Figure 7. Structures of non-ribosomal peptides with anti-HIV activity (70–82).

FIGURE 8
www.frontiersin.org

Figure 8. Structures of non-ribosomal peptides with anti-HIV activity (83–89).

The marine sponge Homophymia sp. was the source of an anti-HIV cyclodepsipeptide, Homophymine A (76). This peptide inhibited the infection of HIV-1 in PBMC cell line with an IC50 of 75 nM (Zampella et al., 2008). Six depsipeptides Celebesides A-C (77–79) and Theopapuamides B-D (80–82) were isolated from an Indonesian sponge S. mirabilis. Compound (77) neutralized HIV-1 with an IC50 value of 1.9 ± 0.4 μg/mL, while the non-phosphorylated analog Celebeside C was inactive at concentrations as high as 50 μg/mL. Theopapuamides A-C displayed cytotoxicity against human colon carcinoma (HCT-116) cells with IC50 values between 2.1 and 4.0 μg/mL, and antifungal activity against wild type and amphotericin B-resistant strains of C. albicans at 1–5 μg/disk (Plaza et al., 2008). The deep-water specimens of T. swinhoei and Theonella cupola (Mutremdiu Reef, Palau) gave sulphated cyclic depsipeptide, Mutremdamide A (83) and 6 N-methylated peptides Koshikamides C–H (84–89). Cyclic koshikamides F and H inhibited HIV-1 entry at IC50 values of 2.3 and 5.5 μM, respectively, while their linear counterparts were inactive (Plaza et al., 2010).

Anti-Inflammatory NRPs (Figure 9)

Marine sponge S. symbiotica collected from Biaro Island, Indonesia, alongwith its symbiont marine red alga (Rhodophyta) Ceratodictyon spongiosum gave thiazole-containing cyclic heptapeptide, Ceratospongamide (90). Compound (90) consists of two l-phenylalanine residues, one (l-isoleucine)-l-methyloxazoline residue, one l-proline residue, and one (l-proline) thiazole residue. The trans-isomer of ceratospongamide exhibits potent inhibition of sPLA2 expression in a cell-based model for anti-inflammation at ED50 32 nM (Tan et al., 2000). Two cyclic depsipeptides, Halipeptins A and B (91,92) were obtained from marine sponge Haliclona sp. Only halipeptins A displayed in vivo potent anti-inflammatory activity (mice at the dose of 300 μg/kg [i.p.]) (Randazzo et al., 2001). A Solomon Lithistid sponge T. swinhoei was the source of 2 new cyclopeptides Perthamides C and D with potent anti-inflammatory (93,94) (Festa et al., 2009). Cyclic peptides, Solomonamides A and B (95,96), were separated out from the marine sponge T. swinhoei; however, only compound (86) showed anti-inflammatory activity (Festa et al., 2011). The marine sponge S. massa produced a cyclic peptide Stylissatin A (97) that inhibited nitric oxide production in LPS-stimulated murine macrophage RAW264.7 cells with an IC50 value of 87 μM (Kita et al., 2013).

FIGURE 9
www.frontiersin.org

Figure 9. Structures of non-ribosomal peptides with anti-inflammatory activity (90–97).

Antimicrobial Agents (Figure 10)

The solitary tunicate, H. aurantium, was the source of a novel antimicrobial peptide Dicynthaurin (98) (Lee I. H. et al., 2001). An antibacterial depsipeptide, Nagahamide A (99), was discovered from the marine sponge T. swinhoei (Okada et al., 2002). An antimicrobial octapeptide Plicatamide (100) was isolated from S. plicata (Tincu et al., 2003). The marine sponge Latrunculia sp., (Vanuatu Islands) was the source of four new antifungal peptides, Callipeltins F–I (101–104). Callipeltins F–I inhibit the growth of C. albicans (ATCC24433) with a MIC value of 10−4 M (Sepe et al., 2006). Four new peptides, Callipeltins J–M (105–108), were isolated from the marine sponge Latrunculia sp. However, only Callipeltins J and K inhibited the growth of C. albicans with MIC values of ca. 4−10 M (D'Auria et al., 2007). Two new linear tetrapeptides, Citronamides A (109) and B (110), were isolated from the Australian sponge C. astra. Only citronamides A showed moderate antifungal activity against Saccharomyces cerevisiae at MIC value of 8 μg/mL (Carroll et al., 2009).

FIGURE 10
www.frontiersin.org

Figure 10. Structures of antimicrobial non-ribosomal peptides (98–110).

Miscellaneous (Figure 11)

A cyclic tripeptide Renieramide (111) was isolated from Vanuatu collection of sponge Reniera sp. that showed immunomodulating activity in preliminary tests (Ciasullo et al., 2002). Two nematocidal depsipeptides, Phoriospongin A and B (112 and 113), were isolated from Australian marine sponges Phoriospongia sp. and C. bilamellata. Both compounds have displayed significant nematocidal activity against H. contortus (LD99 = 100, 194 μg/mL, respectively) (Capon et al., 2002).

FIGURE 11
www.frontiersin.org

Figure 11. Structures of non-ribosomal peptides with (111–113).

Biological Aspects, Challenges, and Future Perspectives

Like their structural diversity, metabolites produced from marine sponges and tunicates bind to a variety of cellular targets to elicit their effects. Numerous articles published in recent years highlighting the significance of these metabolites in disease control, the details of their biological significance from molecular recognition perspective have been rather scarce. Although some promising leads have been obtained, the discovery of their cellular targets, molecular interactions, and adverse effects are lacking. In cases where the therapeutic potential has been reported, details of a proper screening approach to identify nucleic acid or protein targets are missing. However, some established metabolites from these sources (see Tables 1, 2) and their derivatives have been examined extensively and their molecular targets are varied. One of the earliest examples in this class is FDA-approved drug Ara-C (cytarabine), which is known to elicit anticancer properties by inhibiting the functions of DNA polymerase (Furth and Cohen, 1968), which ultimately results in stalling DNA synthesis. Another FDA approved related compound Ara-A(vidarabine), which is known to have antiviral properties (active against herpes simplex and varicella zoster viruses), targets viral DNA polymerase (Chadwick et al., 1978) by functioning as mimic of natural nucleotides. Both Ara-C and Ara-A resemble natural cytidine and adenine nucleosides where the structural differences are in the sugar components of the two (arabinose vs. deoxyribose). The natural nucleoside mimics Ara-A and Ara-C are easily phosphorylated as their triphosphate derivatives by kinases and act as terminators of DNA synthesis. Ara-A is also known to impede 3′-end processing of pre-mRNAs by inhibiting cleavage and polyadenylation (Ghoshal and Jacob, 1991; Rose and Jacob, 1978).

Several other molecules that are either FDA approved or in early stages of clinical trials have been identified as anticancer agents with microtubules as their primary molecular targets. The predominance of natural metabolites being microtubule binding agents has been hypothesized as evolutionary response to predation by plants and animals (Dumontet and Jordan, 2010). Some of these molecules, such as discodermolide, are among the first non-taxane stabilizers of microtubules (Mooberry et al., 2004). The microtubule stabilizers act by enhancing microtubule polymerization at high concentrations. Discodermolide has been known to bind to tubulin dimers in a stoichiometric ratio. Competitive binding experiments have shown that it blocks taxol binding and is a much stronger binder of microtubules than taxol (Kowalski et al., 1997). The microtubule binding of Tau proteins is interfered by discodermolide (Kar et al., 2003). Similarly, laulimalide showed properties very similar to paclitaxel where it helped in enhancing tubulin assembly (Gapud et al., 2004). However, laulimalide modulation of microtubule assembly in C. elegans is dose dependent where it stabilization effects were observed only at concentrations higher than 100 nM (Bajaj and Srayko, 2013).

The antiviral effect of homophymine A has been established by measuring the reverse transcriptase activity in HIV-infected primary peripheral blood mononuclear cells (Zampella et al., 2008). The reverse transcriptase activity is exhibited by 2 classes of molecules: one that directly competes with natural nucleotide triphosphates and the other that either directly blocks the catalytic reactions or by allosteric binding that leads to structural changes in the viral enzyme. Since homophymine A lacks structural features to act as mimics of natural nucleotide triphosphates, it is likely to impede the catalytic activity of the enzyme by direct binding.

A tunicate-derived metabolite trabectedin (ET-743) uses DNA binding to exert its anticancer properties. Trabectin binds to the GC rich regions in the B-DNA where it uses its carbolinamine moiety to form adduct with the exocylic amine (N-2) of guanine (Pommier et al., 1996) and covers 3 base pairs during this process (Marco et al., 2006). Unlike B-DNA minor groove binders, such as Hoechst 33258, which binds snugly along the minor groove curvature with high-affinity (Haq et al., 1997), trabectedin only uses part of its structure to make necessary contacts for the antitumor action (D'Incalci and Galmarini, 2010).

Despite these advances in determining the mode of their binding, a large number of recently discovered metabolites are still not explored to assess it functional capabilities. In the past, well-known anti-retroviral drug zidovudine, which was initially thought to be functionally inert, turned out as excellent therapeutic agent. Such discoveries are possible only when a rational screening design is aimed to asses it full potential as a drug. For example, compounds that have structural regions favorable for protein binding should be screened against all potential protein targets. Similarly, compounds that show preference toward nucleic acid binding should be screened using assays such as competition dialysis that establish a preferential nucleic acid target. Such approaches not only determine the best target for a particular compound but also shed light to its secondary targets, which may be helpful in dealing with toxicity issues. Current target design of marine and tunicate metabolites clearly need to take these approaches.

Some of the metabolites that have weaker binding to a target or have poor bioavailability can be improved by nano-encapsulation techniques. Additionally, DNA binding metabolites can be chemically modified to enhance their affinity using multi-recognition of the target (Willis and Arya, 2010), which has led to remarkable enhancement in the affinity of double,(Arya et al., 2003), triple (Arya and Willis, 2003), and four-stranded DNA helical structures (Ranjan et al., 2013).

Conclusion

Extreme environment of the ocean plays a vital role in exploring and studying marine bio-resources and their bio-actives. The large biodiversity of the sea serves as a huge resource for developing potential drugs with promising pharmacological activities. The significance of marine-derived secondary metabolites has recently been highlighted by introduction of Prialt and Yondelis to the market. In the past three decades, numerous NRPs with unique chemical structures and varied biological activities have been discovered from marine sponges and tunicates as described in this. Some of these exhibit strong potential to be developed as a new drug. However, none of the NRPs highlighted in this review have been successfully marketed as therapeutics. To translate bioactivity of these important metabolites into therapeutically significant outcomes, it is crucial to further unravel their modes of action and measure their toxicity. Since the majority of these studies have been focused on in vitro bioassays and elucidation of the chemical structures only, a complete examination of their biological target selectivity is required. Nevertheless, large-scale production of these NRPs for clinical use is a real challenge. Therefore, environmentally sound and economically feasible alternatives are required. To counter these challenges, many strategies have been established.

Chemical synthesis of NRPs is among the first strategies to be used. However, the structural complexity limits its chemical synthesis and has resulted in only a few successful achievements (e.g., analgesic drug ziconotide; Olivera, 2000). A second strategy uses screening the pharmacological significance of NRPs and subsequently attempting to define the critical pharmacophore that can result in practical drugs based on a marine prototype via chemical synthesis, degradation, modification, or a combination of these. Aquaculture of the source organisms has also been used to secure a sustainable supply of active compounds. However, in most cases, the biomass currently generated is still far from the requirement from an industrial perspective (Mendola, 2000). Identification and large-scale culturing of true producers that are known to thrive within the tissues of marine invertebrates (sponge or tunicate) is an intriguing strategy. However, to date only 5% or less of the symbiotic microbes present in marine specimens can be cultivated under standard conditions. Consequently, molecular approaches such as transfer of biosynthetic gene clusters to a vector suitable for large-scale fermentation could be used to avoid obstacles in culturing symbiotic bacteria. Enzyme technology and solid-phase peptide synthesis offer particularly promising alternatives to generate variety of unique peptides using native peptide as a template. Besides, combinations of chemical synthesis and biosynthetic technologies have potential to accelerate the discovery of novel drugs derived from sponge and their microbial association in future.

Author Contributions

SD reviewed the collected information critically. SA collected the relevant information from various sources including databases like Scifider. AA gave the concept of the work.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

Abraham, E., and Newton, G. (1961). The structure of cephalosporin C. Biochem. J. 79:377. doi: 10.1042/bj0790377

PubMed Abstract | CrossRef Full Text | Google Scholar

Aoki, S., Cao, L., Matsui, K., Rachmat, R., Akiyama, S.-I., and Kobayashi, M. (2004). Kendarimide A, a novel peptide reversing P-glycoprotein-mediated multidrug resistance in tumor cells, from a marine sponge of Haliclona sp. Tetrahedron 60, 7053–7059. doi: 10.1016/j.tet.2003.07.020

CrossRef Full Text | Google Scholar

Arai, M., Yamano, Y., Fujita, M., Setiawan, A., and Kobayashi, M. (2012). Stylissamide X, a new proline-rich cyclic octapeptide as an inhibitor of cell migration, from an Indonesian marine sponge of Stylissa sp. Bioorg. Med. Chem. Lett. 22, 1818–1821. doi: 10.1016/j.bmcl.2011.10.023

PubMed Abstract | CrossRef Full Text | Google Scholar

Arya, D. P., and Willis, B. (2003). Reaching into the major groove of B-DNA: synthesis and nucleic acid binding of a Neomycin-Hoechst 33258 conjugate. J. Am. Chem. Soc. 125, 12398–12399. doi: 10.1021/ja036742k

PubMed Abstract | CrossRef Full Text | Google Scholar

Arya, D. P., Xue, L., and Tennant, P. (2003). Combining the best in triplex recognition: synthesis and nucleic acid binding of a BQQ-Neomycin conjugate. J. Am. Chem. Soc. 125, 8070–8071. doi: 10.1021/ja034241t

PubMed Abstract | CrossRef Full Text | Google Scholar

Bajaj, M., and Srayko, M. (2013). Laulimalide induces dose-dependent modulation of microtubule behaviour in the C. elegans embryo. PLoS ONE 8:e71889. doi: 10.1371/journal.pone.0071889

PubMed Abstract | CrossRef Full Text | Google Scholar

Bewley, C., Holland, N., and Faulkner, D. (1996). Two classes of metabolites from Theonella swinhoei are localized in distinct populations of bacterial symbionts. Experientia 52, 716–722. doi: 10.1007/BF01925581

PubMed Abstract | CrossRef Full Text | Google Scholar

Brennan, M. R., Costello, C. E., Maleknia, S. D., Pettit, G. R., and Erickson, K. L. (2008). Stylopeptide 2, a proline-rich cyclodecapeptide from the sponge Stylotella sp. J. Nat. Prod. 71, 453–456. doi: 10.1021/np0704856

PubMed Abstract | CrossRef Full Text | Google Scholar

Brusca, R. C., Brusca, G. J., and Haver, N. J. (1990). Invertebrates. Sunderland, MA: Sinauer Associates.

Google Scholar

Bultel-Poncé, V., Berge, J.-P., Debitus, C., Nicolas, J.-L., and Guyot, M. (1999). Metabolites from the sponge-associated bacterium Pseudomonas species. Mar. Biotechnol. 1, 384–390. doi: 10.1007/PL00011792

PubMed Abstract | CrossRef Full Text | Google Scholar

Bultel-Poncé, V., Debitus, C., Berge, J.-P., Cerceau, C., and Guyot, M. (1998). Metabolites from the sponge-associated bacterium Micrococcus luteus. J. Mar. Biotechnol. 6, 233–236.

PubMed Abstract | Google Scholar

Capon, R. J., Ford, J., Lacey, E., Gill, J. H., Heiland, K., and Friedel, T. (2002). Phoriospongin A and B: two new nematocidal depsipeptides from the Australian marine sponges Phoriospongia sp. and Callyspongia bilamellata. J. Nat. Prod. 65, 358–363. doi: 10.1021/np010329d

PubMed Abstract | CrossRef Full Text | Google Scholar

Carroll, A. R., Duffy, S., and Avery, V. M. (2009). Citronamides A and B, tetrapeptides from the australian sponge Citronia astra. J. Nat. Prod. 72, 764–768. doi: 10.1021/np800832w

PubMed Abstract | CrossRef Full Text | Google Scholar

Chadwick, R. G., Bassendine, M. F., Crawford, E. M., Thomas, H. C., and Sherlock, S. (1978). Hbsag-positive chronic liver disease: inhibition of DNA polymerase activity by vidarabine. Br. Med. J. 2, 531–533. doi: 10.1136/bmj.2.6136.531

PubMed Abstract | CrossRef Full Text | Google Scholar

Chevallier, C., Richardson, A. D., Edler, M. C., Hamel, E., Harper, M. K., and Ireland, C. M. (2003). A new cytotoxic and tubulin-interactive milnamide derivative from a marine sponge Cymbastela sp. Org. Lett. 5, 3737–3739. doi: 10.1021/ol035476c

PubMed Abstract | CrossRef Full Text | Google Scholar

Ciasullo, L., Casapullo, A., Cutignano, A., Bifulco, G., Debitus, C., Hooper, J., et al. (2002). Renieramide, a cyclic tripeptide from the Vanuatu sponge Reniera n. sp. J. Nat. Prod. 65, 407–410. doi: 10.1021/np010383u

PubMed Abstract | CrossRef Full Text | Google Scholar

D'Auria, M. V., Sepe, V., D'Orsi, R., Bellotta, F., Debitus, C., and Zampella, A. (2007). Isolation and structural elucidation of callipeltins J–M: antifungal peptides from the marine sponge Latrunculia sp. Tetrahedron 63, 131–140. doi: 10.1016/j.tet.2006.10.032

CrossRef Full Text | Google Scholar

Davis, R. A., Mangalindan, G. C., Bojo, Z. P., Antemano, R. R., Rodriguez, N. O., Concepcion, G. P., et al. (2004). Microcionamides A and B, bioactive peptides from the Philippine sponge Clathria (Thalysias) abietina. J. Org. Chem. 69, 4170–4176. doi: 10.1021/jo040129h

PubMed Abstract | CrossRef Full Text | Google Scholar

de Crécy-Lagard, V., Blanc, V., Gil, P., Naudin, L., Lorenzon, S., Famechon, A., et al. (1997). Pristinamycin I biosynthesis in Streptomyces pristinaespiralis: molecular characterization of the first two structural peptide synthetase genes. J. Bacteriol. 179, 705–713.

PubMed Abstract | Google Scholar

D'Incalci, M., and Galmarini, C. M. (2010). A review of trabectedin (ET-743): a unique mechanism of action. Mol. Cancer Therap. 9, 2157–2163. doi: 10.1158/1535-7163.MCT-10-0263

PubMed Abstract | CrossRef Full Text | Google Scholar

Domenech, O., Francius, G., Tulkens, P. M., Van Bambeke, F., Dufrêne, Y., and Mingeot-Leclercq, M.-P. (2009). Interactions of oritavancin, a new lipoglycopeptide derived from vancomycin, with phospholipid bilayers: effect on membrane permeability and nanoscale lipid membrane organization. Biochim. Biophys. Acta 1788, 1832–1840. doi: 10.1016/j.bbamem.2009.05.003

PubMed Abstract | CrossRef Full Text | Google Scholar

Dumontet, C., and Jordan, M. A. (2010). Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat. Rev. Drug Discov. 9, 790–803. doi: 10.1038/nrd3253

PubMed Abstract | CrossRef Full Text | Google Scholar

Elyakov, G., Kuznetsova, T., Mikhailov, V., Maltsev, I., Voinov, V., and Fedoreyev, S. (1991). Brominated diphenyl ethers from a marine bacterium associated with the sponge Dysidea sp. Experientia 47, 632–633. doi: 10.1007/BF01949894

CrossRef Full Text | Google Scholar

Fenical, W. (1976). Geranyl hydroquinone, a cancer-protective agent from the tunicate Aplidium species. Food Drugs Sea Proc. 4, 388–394.

Fernández, R., Martín, M. J., Rodríguez-Acebes, R., Reyes, F., Francesch, A., and Cuevas, C. (2008). Diazonamides C–E, new cytotoxic metabolites from the ascidian Diazona sp. Tetrahedron Lett. 49, 2283–2285. doi: 10.1016/j.tetlet.2008.02.012

CrossRef Full Text | Google Scholar

Festa, C., De Marino, S., Sepe, V., D'Auria, M. V., Bifulco, G., Débitus, C., et al. (2011). Solomonamides A and B, new anti-inflammatory peptides from Theonella swinhoei. Org. Lett. 13, 1532–1535. doi: 10.1021/ol200221n

PubMed Abstract | CrossRef Full Text | Google Scholar

Festa, C., De Marino, S., Sepe, V., Monti, M. C., Luciano, P., D'auria, M. V., et al. (2009). Perthamides C and D, two new potent anti-inflammatory cyclopeptides from a Solomon Lithistid sponge Theonella swinhoei. Tetrahedron 65, 10424–10429. doi: 10.1016/j.tet.2009.10.026

CrossRef Full Text | Google Scholar

Finking, R., and Marahiel, M. A. (2004). Biosynthesis of nonribosomal peptides1. Annu. Rev. Microbiol. 58, 453–488. doi: 10.1146/annurev.micro.58.030603.123615

PubMed Abstract | CrossRef Full Text | Google Scholar

Fu, X., Su, J., and Zeng, L. (2000). Prepatellamide A, a new cyclic peptide from the ascidian Lissoclinum patella. Sci. China Ser. B Chem. 43, 643–648. doi: 10.1007/BF02969512

CrossRef Full Text | Google Scholar

Furth, J. J., and Cohen, S. S. (1968). Inhibition of mammalian DNA polymerase by the 5′-triphosphate of 1-β-d-arabinofuranosylcytosine and the 5′-triphosphate of 9-β-d-arabinofuranosyladenine. Cancer Res. 28, 2061–2067.

PubMed Abstract | Google Scholar

Gapud, E. J., Bai, R., Ghosh, A. K., and Hamel, E. (2004). Laulimalide and paclitaxel: a comparison of their effects on tubulin assembly and their synergistic action when present simultaneously. Mol. Pharmacol. 66, 113–121. doi: 10.1124/mol.66.1.113

PubMed Abstract | CrossRef Full Text

Ghoshal, K., and Jacob, S. T. (1991). Ara-ATP impairs 3′-end processing of pre-mRNAs by inhibiting both cleavage and polyadenylation. Nucleic Acids Res. 19, 5871–5875. doi: 10.1093/nar/19.21.5871

PubMed Abstract | CrossRef Full Text | Google Scholar

Hamada, T., Matsunaga, S., Yano, G., and Fusetani, N. (2005). Polytheonamides A and B, highly cytotoxic, linear polypeptides with unprecedented structural features, from the marine sponge, Theonella swinhoei. J. Am. Chem. Soc. 127, 110–118. doi: 10.1021/ja045749e

PubMed Abstract | CrossRef Full Text | Google Scholar

Haq, I., Ladbury, J. E., Chowdhry, B. Z., Jenkins, T. C., and Chaires, J. B. (1997). Specific binding of Hoechst 33258 to the d(CGCAAATTTGCG)2 duplex: calorimetric and spectroscopic studies1. J. Mol. Biol. 271, 244–257.

PubMed Abstract | Google Scholar

Hentschel, U., Hopke, J., Horn, M., Friedrich, A. B., Wagner, M., Hacker, J., et al. (2002). Molecular evidence for a uniform microbial community in sponges from different oceans. Appl. Environ. Microbiol. 68, 4431–4440. doi: 10.1128/AEM.68.9.4431-4440.2002

PubMed Abstract | CrossRef Full Text | Google Scholar

Hentschel, U., Schmid, M., Wagner, M., Fieseler, L., Gernert, C., and Hacker, J. (2001). Isolation and phylogenetic analysis of bacteria with antimicrobial activities from the Mediterranean sponges Aplysina aerophoba and Aplysina cavernicola. FEMS Microbiol. Ecol. 35, 305–312. doi: 10.1111/j.1574-6941.2001.tb00816.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Ibrahim, S. R., Edrada-Ebel, R., Mohamed, G. A., Youssef, D. T., Wray, V., and Proksch, P. (2008). Callyaerin G, a new cytotoxic cyclic peptide from the marine sponge Callyspongia aerizusa. ARKIVOC 12, 164–171. doi: 10.3998/ark.5550190.0009.c18

CrossRef Full Text | Google Scholar

Ibrahim, S. R., Min, C. C., Teuscher, F., Ebel, R., Kakoschke, C., Lin, W., et al. (2010). Callyaerins A–F and H, new cytotoxic cyclic peptides from the Indonesian marine sponge Callyspongia aerizusa. Bioorg. Med. Chem. 18, 4947–4956. doi: 10.1016/j.bmc.2010.06.012

PubMed Abstract | CrossRef Full Text | Google Scholar

Johnson, B. A., Anker, H., and and, Meleney, F. L. (1945). Bacitracin: a new antibiotic produced by a member of the B. subtilis group. Science 102, 376–377. doi: 10.1126/science.102.2650.376

PubMed Abstract | CrossRef Full Text | Google Scholar

Kar, S., Florence, G. J., Paterson, I., and Amos, L. A. (2003). Discodermolide interferes with the binding of tau protein to microtubules. FEBS Lett. 539, 34–36. doi: 10.1016/S0014-5793(03)00181-9

PubMed Abstract | CrossRef Full Text | Google Scholar

Kehraus, S., König, G. M., Wright, A. D., and Woerheide, G. (2002). Leucamide A: a new cytotoxic heptapeptide from the Australian sponge Leucetta microraphis. J. Org. Chem. 67, 4989–4992. doi: 10.1021/jo020058r

PubMed Abstract | CrossRef Full Text | Google Scholar

Kita, M., Gise, B., Kawamura, A., and Kigoshi, H. (2013). Stylissatin A, a cyclic peptide that inhibits nitric oxide production from the marine sponge Stylissa massa. Tetrahedron Lett. 54, 6826–6828. doi: 10.1016/j.tetlet.2013.10.003

CrossRef Full Text | Google Scholar

Kleinkauf, H., and von Döhren, H. (1995). The nonribosomal peptide biosynthetic system—on the origins of structural diversity of peptides, cyclopeptides and related compounds. Antonie Van Leeuwenhoek 67, 229–242. doi: 10.1007/BF00873687

PubMed Abstract | CrossRef Full Text | Google Scholar

Kowalski, R. J., Giannakakou, P., Gunasekera, S. P., Longley, R. E., Day, B. W., and Hamel, E. (1997). The microtubule-stabilizing agent discodermolide competitively inhibits the binding of paclitaxel (taxol) to tubulin polymers, enhances tubulin nucleation reactions more potently than paclitaxel, and inhibits the growth of paclitaxel-resistant cells. Mol. Pharmacol. 52, 613–622.

PubMed Abstract | Google Scholar

Laport, M., Santos, O., and Muricy, G. (2009). Marine sponges: potential sources of new antimicrobial drugs. Curr. Pharm. Biotechnol. 10, 86–105. doi: 10.2174/138920109787048625

PubMed Abstract | CrossRef Full Text | Google Scholar

Lee, I. H., Lee, Y. S., Kim, C. H., Kim, C. R., Hong, T., Menzel, L., et al. (2001). Dicynthaurin: an antimicrobial peptide from hemocytes of the solitary tunicate, Halocynthia aurantium. Biochim. Biophys. Acta 1527, 141–148. doi: 10.1016/S0304-4165(01)00156-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Lee, Y. K., Lee, J.-H., and Lee, H. K. (2001). Microbial symbiosis in marine sponges. J. Microbiol. 39, 254–264.

Google Scholar

Marco, E., David-Cordonnier, M.-H., Bailly, C., Cuevas, C., and Gago, F. (2006). Further insight into the DNA recognition mechanism of trabectedin from the differential affinity of its demethylated analogue ecteinascidin ET729 for the triplet DNA binding site CGA. J. Med. Chem. 49, 6925–6929. doi: 10.1021/jm060640y

PubMed Abstract | CrossRef Full Text | Google Scholar

Maulucci, N., Chini, M. G., Di Micco, S., Izzo, I., Cafaro, E., Russo, A., et al. (2007). Molecular insights into azumamide E histone deacetylases inhibitory activity. J. Am. Chem. Soc. 129, 3007–3012. doi: 10.1021/ja0686256

PubMed Abstract | CrossRef Full Text | Google Scholar

Mayer, A. M., Glaser, K. B., Cuevas, C., Jacobs, R. S., Kem, W., Little, R. D., et al. (2010). The odyssey of marine pharmaceuticals: a current pipeline perspective. Trends Pharmacol. Sci. 31, 255–265. doi: 10.1016/j.tips.2010.02.005

PubMed Abstract | CrossRef Full Text | Google Scholar

Mehbub, M. F., Lei, J., Franco, C., and Zhang, W. (2014). Marine sponge derived natural products between 2001 and 2010: trends and opportunities for discovery of bioactives. Mar. Drugs 12, 4539–4577. doi: 10.3390/md12084539

PubMed Abstract | CrossRef Full Text | Google Scholar

Mendola, D. (2000). “Aquacultural production of bryostatin 1 and ecteinascidin 743,” in Drugs from the Sea, ed N. Fusetani (Basel: Karger), 120–133. doi: 10.1159/000062482

CrossRef Full Text

Menna, M. (2009). Antitumor potential of natural products from Mediterranean ascidians. Phytochem. Rev. 8, 461–472. doi: 10.1007/s11101-009-9131-y

CrossRef Full Text | Google Scholar

Miao, V., Coeffet-Legal, M.-F., Brian, P., Brost, R., Penn, J., Whiting, A., et al. (2005). Daptomycin biosynthesis in Streptomyces roseosporus: cloning and analysis of the gene cluster and revision of peptide stereochemistry. Microbiology 151, 1507–1523. doi: 10.1099/mic.0.27757-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Mooberry, S. L., Randall-Hlubek, D. A., Leal, R. M., Hegde, S. G., Hubbard, R. D., Zhang, L., et al. (2004). Microtubule-stabilizing agents based on designed laulimalide analogues. Proc. Natl. Acad. Sci. U.S.A. 101, 8803–8808. doi: 10.1073/pnas.0402759101

PubMed Abstract | CrossRef Full Text | Google Scholar

Murthy, M. R., Mohan, E., and Sadhukhan, A. (1999). Cyclosporin-A production by Tolypocladium inflatum using solid state fermentation. Process Biochem. 34, 269–280. doi: 10.1016/S0032-9592(98)00095-8

CrossRef Full Text | Google Scholar

Nakao, Y., Fujita, M., Warabi, K., Matsunaga, S., and Fusetani, N. (2000). Miraziridine A, a novel cysteine protease inhibitor from the marine sponge Theonella aff. mirabilis 1. J. Am. Chem. Soc. 122, 10462–10463. doi: 10.1021/ja001859j

CrossRef Full Text | Google Scholar

Nakao, Y., Kawatsu, S., Okamoto, C., Okamoto, M., Matsumoto, Y., Matsunaga, S., et al. (2008). Ciliatamides A−C, bioactive lipopeptides from the deep-sea sponge Aaptos ciliata. J. Nat. Prod. 71, 469–472. doi: 10.1021/np8000317

PubMed Abstract | CrossRef Full Text | Google Scholar

Nakao, Y., Kuo, J., Yoshida, W. Y., Kelly, M., and Scheuer, P. J. (2003). More kapakahines from the marine sponge Cribrochalina olemda. Org. Lett. 5, 1387–1390. doi: 10.1021/ol026830u

PubMed Abstract | CrossRef Full Text | Google Scholar

Newman, D. J., and Cragg, G. M. (2016). Natural products as sources of new drugs from 1981 to 2014. J. Nat. Prod. 79, 629–661. doi: 10.1021/acs.jnatprod.5b01055

PubMed Abstract | CrossRef Full Text | Google Scholar

Newman, D. J., and Hill, R. T. (2006). New drugs from marine microbes: the tide is turning. J. Ind. Microbiol. Biotechnol. 33, 539–544. doi: 10.1007/s10295-006-0115-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Oclarit, J., Okada, H., Ohta, S., Kaminura, K., Yamaoka, Y., Iizuka, T., et al. (1994). Anti-bacillus substance in the marine sponge, Hyatella species, produced by an associated Vibrio species bacterium. Microbios 78, 7.

PubMed Abstract | Google Scholar

Okada, Y., Matsunaga, S., van Soest, R. W., and Fusetani, N. (2002). Nagahamide A, an antibacterial depsipeptide from the marine sponge Theonella swinhoei 1. Org. Lett. 4, 3039–3042. doi: 10.1021/ol0262791

PubMed Abstract | CrossRef Full Text | Google Scholar

Oku, N., Gustafson, K. R., Cartner, L. K., Wilson, J. A., Shigematsu, N., Hess, S., et al. (2004). Neamphamide A, a new HIV-inhibitory depsipeptide from the Papua New Guinea marine sponge Neamphius huxleyi. J. Nat. Prod. 67, 1407–1411. doi: 10.1021/np040003f

PubMed Abstract | CrossRef Full Text | Google Scholar

Olivera, B. M. (2000). “ω- Conotoxin MVIIA: from marine snail venom to analgesic drug,” in Drugs from the Sea, ed N. Fusetani (Basel: Karger), 74–85. doi: 10.1159/000062483

PubMed Abstract | CrossRef Full Text

Olson, J. B., and McCarthy, P. J. (2005). Associated bacterial communities of two deep-water sponges. Aquat. Microb. Ecol. 39, 47–55. doi: 10.3354/ame039047

CrossRef Full Text | Google Scholar

Paulus, H., and Gray, E. (1964). The biosynthesis of polymyxin B by growing cultures of Bacillus polymyxa. J. Biol. Chem. 239, 865–871.

PubMed Abstract | Google Scholar

Perez, L. J., and Faulkner, D. J. (2003). Bistratamides EJ, modified cyclic hexapeptides from the Philippines ascidian Lissoclinum bistratum. J. Nat. Prod. 66, 247–250. doi: 10.1021/np0204601

PubMed Abstract | CrossRef Full Text | Google Scholar

Pettit, G. R., and Tan, R. (2005). Isolation and structure of Phakellistatin 14 from the Western Pacific marine sponge Phakellia sp., 1. J. Nat. Prod. 68, 60–63. doi: 10.1021/np040092w

PubMed Abstract | CrossRef Full Text | Google Scholar

Plaza, A., Bifulco, G., Keffer, J. L., Lloyd, J. R., Baker, H. L., and Bewley, C. A. (2008). Celebesides A−C and theopapuamides B−D, depsipeptides from an Indonesian sponge that inhibit HIV-1 entry. J. Org. Chem. 74, 504–512. doi: 10.1021/jo802232u

PubMed Abstract | CrossRef Full Text | Google Scholar

Plaza, A., Bifulco, G., Masullo, M., Lloyd, J. R., Keffer, J. L., Colin, P. L., et al. (2010). Mutremdamide A and koshikamides C−H, peptide inhibitors of HIV-1 entry from different Theonella species. J. Org. Chem. 75, 4344–4355. doi: 10.1021/jo100076g

PubMed Abstract | CrossRef Full Text | Google Scholar

Plaza, A., Gustchina, E., Baker, H. L., Kelly, M., and Bewley, C. A. (2007). Mirabamides A–D, depsipeptides from the sponge Siliquariaspongia mirabilis that inhibit HIV-1 fusion. J. Nat. Prod. 70, 1753–1760. doi: 10.1021/np070306k

PubMed Abstract | CrossRef Full Text | Google Scholar

Pommier, Y., Kohlhagen, G., Bailly, C., Waring, M., Mazumder, A., and Kohn, K. W. (1996). DNA Sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the caribbean tunicate Ecteinascidia turbinata. Biochemistry 35, 13303–13309. doi: 10.1021/bi960306b

PubMed Abstract | CrossRef Full Text | Google Scholar

Prasad, P., Aalbersberg, W., Feussner, K.-D., and Van Wagoner, R. M. (2011). Papuamides E and F, cytotoxic depsipeptides from the marine sponge Melophlus sp. Tetrahedron 67, 8529–8531. doi: 10.1016/j.tet.2011.08.100

PubMed Abstract | CrossRef Full Text | Google Scholar

Qureshi, A., Colin, P. L., and Faulkner, D. J. (2000). Microsclerodermins F–I, antitumor and antifungal cyclic peptides from the lithistid sponge Microscleroderma sp. Tetrahedron 56, 3679–3685. doi: 10.1016/S0040-4020(00)00286-6

CrossRef Full Text | Google Scholar

Randazzo, A., Bifulco, G., Giannini, C., Bucci, M., Debitus, C., Cirino, G., et al. (2001). Halipeptins A and B: two novel potent anti-inflammatory cyclic depsipeptides from the Vanuatu marine sponge Haliclona species. J. Am. Chem. Soc. 123, 10870–10876. doi: 10.1021/ja010015c

PubMed Abstract | CrossRef Full Text | Google Scholar

Ranjan, N., Davis, E., Xue, L., and Arya, D. P. (2013). Dual recognition of the human telomeric G-quadruplex by a Neomycin-anthraquinone conjugate. Chem. Commun. 49, 5796–5798. doi: 10.1039/c3cc42721h

PubMed Abstract | CrossRef Full Text | Google Scholar

Rashid, M. A., Gustafson, K. R., Boswell, J. L., and Boyd, M. R. (2000). Haligramides A and B, two new cytotoxic hexapeptides from the marine sponge Haliclona nigra. J. Nat. Prod. 63, 956–959. doi: 10.1021/np000051+

PubMed Abstract | CrossRef Full Text | Google Scholar

Rashid, M. A., Gustafson, K. R., Cartner, L. K., Shigematsu, N., Pannell, L. K., and Boyd, M. R. (2001). Microspinosamide, a new HIV-inhibitory cyclic depsipeptide from the marine sponge Sidonops microspinosa 1. J. Nat. Prod. 64, 117–121. doi: 10.1021/np0002379

PubMed Abstract | CrossRef Full Text | Google Scholar

Ratnayake, A. S., Bugni, T. S., Feng, X., Harper, M. K., Skalicky, J. J., Mohammed, K. A., et al. (2006). Theopapuamide, a cyclic depsipeptide from a Papua New Guinea lithistid sponge Theonella swinhoei. J. Nat. Prod. 69, 1582–1586. doi: 10.1021/np060229d

PubMed Abstract | CrossRef Full Text | Google Scholar

Rose, K. M., and Jacob, S. T. (1978). Selective inhibition of RNA polyadenylation by Ara-ATP in vitro: a possible mechanism for antiviral action of Ara-A. Biochem. Biophys. Res. Commun. 81, 1418–1424. doi: 10.1016/0006-291X(78)91294-9

PubMed Abstract | CrossRef Full Text | Google Scholar

Rudi, A., Chill, L., Aknin, M., and Kashman, Y. (2003). Didmolamide A and B, two new cyclic hexapeptides from the marine ascidian Didemnum molle. J. Nat. Prod. 66, 575–577. doi: 10.1021/np020531w

PubMed Abstract | CrossRef Full Text | Google Scholar

Ruppert, E., and Fox, R. (2004). Invertebrate Zoology: A Functional Evolutionary Approach (of RD Barnes' Invertebrate Zoology). Belmont, CA: Brooks/Cole.

Schmidt, E. W., Obraztsova, A., Davidson, S., Faulkner, D., and Haygood, M. (2000). Identification of the antifungal peptide-containing symbiont of the marine sponge Theonella swinhoei as a novel δ-proteobacterium,“Candidatus Entotheonella palauensis”. Mar. Biol. 136, 969–977. doi: 10.1007/s002270000273

CrossRef Full Text | Google Scholar

Schmidt, E. W., Raventos-Suarez, C., Bifano, M., Menendez, A. T., Fairchild, C. R., and Faulkner, D. J. (2004). Scleritodermin A, a cytotoxic cyclic peptide from the lithistid sponge Scleritoderma nodosum. J. Nat. Prod. 67, 475–478. doi: 10.1021/np034035z

PubMed Abstract | CrossRef Full Text | Google Scholar

Sepe, V., D'Orsi, R., Borbone, N., D'auria, M. V., Bifulco, G., Monti, M. C., et al. (2006). Callipeltins F–I: new antifungal peptides from the marine sponge Latrunculia sp. Tetrahedron 62, 833–840. doi: 10.1016/j.tet.2005.10.058

CrossRef Full Text | Google Scholar

Somma, S., Gastaldo, L., and Corti, A. (1984). Teicoplanin, a new antibiotic from Actinoplanes teichomyceticus nov. sp. Antimicrob. Agents Chemother. 26, 917–923. doi: 10.1128/AAC.26.6.917

PubMed Abstract | CrossRef Full Text | Google Scholar

Sonnenschein, R. N., Farias, J. J., Tenney, K., Mooberry, S. L., Lobkovsky, E., Clardy, J., et al. (2004). A further study of the cytotoxic constituents of a milnamide-producing sponge. Org. Lett. 6, 779–782. doi: 10.1021/ol036446c

PubMed Abstract | CrossRef Full Text | Google Scholar

Stark, W., Higgens, C., Wolfe, R., Hoehn, M., and McGuire, J. (1962). Capreomycin, a new antimycobacterial agent produced by Streptomyces capreolus sp. n. Antimicrob. Agents Chemother. 1962, 596–606.

Steele, J. H. (1985). A comparison of terrestrial and marine ecological systems. Nature 313, 355–358. doi: 10.1038/313355a0

CrossRef Full Text | Google Scholar

Stierle, A., Cardellina, I. I. J., and Singleton, F. (1988). A marine Micrococcus produces metabolites ascribed to the sponge Tedania ignis. Experientia 44, 1021–1021. doi: 10.1007/BF01939910

PubMed Abstract | CrossRef Full Text | Google Scholar

Tabudravu, J., Morris, L. A., Kettenes-Van Den Bosch, J. J., and Jaspars, M. (2001). Wainunuamide, a histidine-containing proline-rich cyclic heptapeptide isolated from the Fijian marine sponge Stylotella aurantium. Tetrahedron Lett. 42, 9273–9276. doi: 10.1016/S0040-4039(01)01993-1

CrossRef Full Text | Google Scholar

Tabudravu, J. N., Morris, L. A., Kettenes-van den Bosch, J. J., and Jaspars, M. (2002). Axinellin C, a proline-rich cyclic octapeptide isolated from the Fijian marine sponge Stylotella aurantium. Tetrahedron 58, 7863–7868. doi: 10.1016/S0040-4020(02)00898-0

CrossRef Full Text | Google Scholar

Tan, L. T., Williamson, R. T., Gerwick, W. H., Watts, K. S., McGough, K., and Jacobs, R. (2000). cis, cis-and trans, trans-Ceratospongamide, new bioactive cyclic heptapeptides from the Indonesian red alga Ceratodictyon spongiosum and symbiotic sponge Sigmadocia symbiotica. J. Org. Chem. 65, 419–425. doi: 10.1021/jo991165x

PubMed Abstract | CrossRef Full Text | Google Scholar

Tanaka, C., Tanaka, J., Bolland, R. F., Marriott, G., and Higa, T. (2006). Seragamides A–F, new actin-targeting depsipeptides from the sponge Suberites japonicus Thiele. Tetrahedron 62, 3536–3542. doi: 10.1016/j.tet.2006.01.099

CrossRef Full Text | Google Scholar

Thomas, T. R. A., Kavlekar, D. P., and Lokabharathi, P. A. (2010). Marine drugs from sponge-microbe association—a review. Mar. Drugs 8, 1417–1468. doi: 10.3390/md8041417

PubMed Abstract | CrossRef Full Text | Google Scholar

Tincu, J. A., Menzel, L. P., Azimov, R., Sands, J., Hong, T., Waring, A. J., et al. (2003). Plicatamide, an antimicrobial octapeptide from Styela plicata hemocytes. J. Biol. Chem. 278, 13546–13553. doi: 10.1074/jbc.M211332200

PubMed Abstract | CrossRef Full Text | Google Scholar

Ueda, H., Nakajima, H., Hori, Y., Fujita, T., Nishimura, M., Goto, T., et al. (1994). FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties, and antitumor activity. J. Antibiot. 47, 301–310. doi: 10.7164/antibiotics.47.301

PubMed Abstract | CrossRef Full Text | Google Scholar

Umezawa, H., Maeda, K., Takeuchi, T., and Okami, Y. (1966). New antibiotics, bleomycin A and B. J. Antibiot. 19, 200.

PubMed Abstract | Google Scholar

Unson, M., Holland, N., and Faulkner, D. (1994). A brominated secondary metabolite synthesized by the cyanobacterial symbiont of a marine sponge and accumulation of the crystalline metabolite in the sponge tissue. Mar. Biol. 119, 1–11. doi: 10.1007/BF00350100

CrossRef Full Text | Google Scholar

Van Wageningen, A. A., Kirkpatrick, P. N., Williams, D. H., Harris, B. R., Kershaw, J. K., Lennard, N. J., et al. (1998). Sequencing and analysis of genes involved in the biosynthesis of a vancomycin group antibiotic. Chem. Biol. 5, 155–162. doi: 10.1016/S1074-5521(98)90060-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Vervoort, H., Fenical, W., and Epifanio, R. D. A. (2000). Tamandarins A and B: new cytotoxic depsipeptides from a Brazilian ascidian of the family Didemnidae. J. Org. Chem. 65, 782–792. doi: 10.1021/jo991425a

PubMed Abstract | CrossRef Full Text | Google Scholar

Vicente, J., Vera, B., Rodríguez, A. D., Rodríguez-Escudero, I., and Raptis, R. G. (2009). Euryjanicin A: a new cycloheptapeptide from the Caribbean marine sponge Prosuberites laughlini. Tetrahedron Lett. 50, 4571–4574. doi: 10.1016/j.tetlet.2009.05.067

PubMed Abstract | CrossRef Full Text | Google Scholar

Vinothkumar, S., and Parameswaran, P. (2013). Recent advances in marine drug research. Biotechnol. Adv. 31, 1826–1845. doi: 10.1016/j.biotechadv.2013.02.006

PubMed Abstract | CrossRef Full Text | Google Scholar

Waksman, S. A., and Woodruff, H. B. (1940). Bacteriostatic and bactericidal substances produced by a soil actinomyces. Exp. Biol. Med. 45, 609–614. doi: 10.3181/00379727-45-11768

CrossRef Full Text | Google Scholar

Webster, N. S., Wilson, K. J., Blackall, L. L., and Hill, R. T. (2001). Phylogenetic diversity of bacteria associated with the marine sponge Rhopaloeides odorabile. Appl. Environ. Microbiol. 67, 434–444. doi: 10.1128/AEM.67.1.434-444.2001

PubMed Abstract | CrossRef Full Text | Google Scholar

Wilkinson, C. (1978). Microbial associations in sponges. III. Ultrastructure of the in situ associations in coral reef sponges. Mar. Biol. 49, 177–185. doi: 10.1007/BF00387117

CrossRef Full Text | Google Scholar

Wilkinson, C. R., Nowak, M., Austin, B., and Colwell, R. R. (1981). Specificity of bacterial symbionts in Mediterranean and Great Barrier Reef sponges. Microb. Ecol. 7, 13–21. doi: 10.1007/BF02010474

PubMed Abstract | CrossRef Full Text | Google Scholar

Williams, D. E., Austin, P., Diaz-Marrero, A. R., Soest, R. V., Matainaho, T., Roskelley, C. D., et al. (2005). Neopetrosiamides, peptides from the marine sponge Neopetrosia sp. that inhibit amoeboid invasion by human tumor cells. Org. Lett. 7, 4173–4176. doi: 10.1021/ol051524c

PubMed Abstract | CrossRef Full Text | Google Scholar

Williams, D. E., Yu, K., Behrisch, H. W., Van Soest, R., and Andersen, R. J. (2009). Rolloamides A and B, cytotoxic cyclic heptapeptides isolated from the Caribbean marine sponge Eurypon laughlini. J. Nat. Prod. 72, 1253–1257. doi: 10.1021/np900121m

PubMed Abstract | CrossRef Full Text | Google Scholar

Willis, B., and Arya, D. P. (2010). Triple recognition of B-DNA by a Neomycin−Hoechst 33258−Pyrene conjugate. Biochemistry 49, 452–469. doi: 10.1021/bi9016796

PubMed Abstract | CrossRef Full Text | Google Scholar

Woo, J.-K., Jeon, J.-E., Kim, C.-K., Sim, C. J., Oh, D.-C., Oh, K.-B., et al. (2013). Gombamide A, a cyclic thiopeptide from the sponge Clathria gombawuiensis. J. Nat. Prod. 76, 1380–1383. doi: 10.1021/np4003367

PubMed Abstract | CrossRef Full Text | Google Scholar

Wörheide, G., Solé-Cava, A. M., and Hooper, J. N. (2005). Biodiversity, molecular ecology and phylogeography of marine sponges: patterns, implications and outlooks. Integr. Comp. Biol. 45, 377–385. doi: 10.1093/icb/45.2.377

PubMed Abstract | CrossRef Full Text | Google Scholar

Zampella, A., Sepe, V., Luciano, P., Bellotta, F., Monti, M. C., D'Auria, M. V., et al. (2008). Homophymine A, an anti-HIV cyclodepsipeptide from the sponge Homophymia sp. J. Org. Chem. 73, 5319–5327. doi: 10.1021/jo800583b

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: marine ecosystem, sponge, tunicates, marine natural products, non-ribosomal peptides, pharmacology

Citation: Agrawal S, Adholeya A and Deshmukh SK (2016) The Pharmacological Potential of Non-ribosomal Peptides from Marine Sponge and Tunicates. Front. Pharmacol. 7:333. doi: 10.3389/fphar.2016.00333

Received: 23 March 2016; Accepted: 07 September 2016;
Published: 25 October 2016.

Edited by:

George Tegos, Massachusetts General Hospital, USA

Reviewed by:

Donatella De Pascale, National Research Council (CNR), Italy
Pietro Tedesco, National Research Council (CNR), Italy

Copyright © 2016 Agrawal, Adholeya and Deshmukh. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Sunil K. Deshmukh, sunil.deshmukh@teri.res.in

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.