The organisms belonging to the phylum Porifera, known as sponges, are the oldest remnants among the metazoan group. They are found in large numbers in fresh and saltwater habitats, thanks to the visible ability to adapt to drastic environmental and biological changes. These organisms have a simple level of organization, although their cells are specialized in various functions, but not organized to form tissues and organs (van Soest et al., 2012). Among marine organisms, sponges are the most studied, regarding the production of active peptides, a fact justified by the ease of access and collection of these organisms (van Soest et al., 2012). The early appearance and the sessile way of life of these organisms allowed the development of a group of chemical compounds for communication and modulation of cellular functions and defenses (Braekman and Daloze, 1986). In particular, sponges have become a rich source of new AMPs (Pushpanathan et al., 2013).

In terms of antimicrobial activities (e.g., antibacterial, antifungal and anti-HIV), peptides produced by organisms from the phylum Porifera have been divided into two main classes, including depsipeptides and proline-rich cyclic peptides (Vitali, 2018). These classes differ mainly due to the exclusive cyclic nature of proline-rich cyclic peptide members with numerous proline repetitions that trigger high structural rigidity in these peptides (Wang et al., 2014a). By contrast, depsipeptides can present both linear and cyclic (called cyclic depsipeptides) scaffolds (Plaza et al., 2010). Cyclic depsipeptides with anti-viral activities include callipeltins (Figure 4), mirabamides, celebesides, neamphamide A and papuamides (Cyclodepsipeptides from marine sponges: natural agents for drug research.). These peptides share aliphatic tails, a tyrosine-free hydroxyl group, the presence of a 3,4-dimethylglutamine residue, unusual AA repetitions and N-terminal polyketide-derived moieties (Andjelic et al., 2008; Giordano et al., 2018).

From studies carried out with the deep-water species Theonella cupola and T. swinhoei, the linear peptides koshikamides C-E and cyclic depsipeptides koshikamides F-H (Figure 4) were isolated. It was reported that koshikamides F and H inhibited the entry of HIV-1 in low concentrations, while their linear forms (koshikamides C and E) were inactive. The authors suggested that HIV-1 inhibition is due to the presence of the lactone ring with 10 AA residues that forms the structure of koshikamides F and H, but is absent in the linear forms of these peptides (Plaza et al., 2010). Celebesides A-C, cyclic depsipeptides that contain the unusual AAs phosphoserine and 3-carbamoyl threonine, were isolated from Siliquariaspongia mirabilis, and both are considered new marine products. The AA phosphoserine was correlated with the presence of anti-HIV activity in celebesides (Plaza et al., 2009; Giordano et al., 2018). Other peptides with anti-HIV activity isolated from S. mirabilis are mirabamides A–D (Figure 4 and Supplementary Table 1) (Plaza et al., 2007; Giordano et al., 2018). New mirabamides (E–H) were isolated from a sponge of the genus Stelletta, and these compounds also showed anti-HIV action (Lu et al., 2011). The peptides stellettapeptins A and B, isolated from Stelletta sp., are cyclic depsipeptides with anti-HIV activity. These compounds were tested in the human T-cell line CEM-SS infected with HIV-1_RF, in which the anti-HIV activity was evaluated in an XTT-based cell viability assay. Stellettapeptins A and B showed a potent inhibition effect on HIV-1 infection half-maximal effective concentration (EC₅₀) values of 23 and 27 nM, respectively, which means they can be considered as a family of anti-HIV peptides (Shin et al., 2015).

All these cyclic depsipeptides’ features have led to a broad spectrum of biological targets, including viral surface components. For instance, many studies have reported the influence of phosphatidylserine phospholipids on the viral surface for cyclicdepsitepeptides’ anti-viral effects (Andjelic et al., 2008). As mentioned above, these peptides present an atyrosine hydroxyl group that interacts with cholesterol membrane, whereas the aliphatic tails favor the peptides’ insertion into the viral membrane. Although this mechanism has been well described for papuamide A, the potency of other papuamide and miramabide peptides can differ depending on the unusual AA residues present in their structures (Plaza et al., 2007). For instance, it has been shown that the rhamnosylated β-methyltyrosine residue in mirabamide A has a direct influence on the higher potency of this peptide, compared to mirabamide B, C, and D (Plaza et al., 2007). Moreover, mirabamide B was found to be the least potent variant, as this is the only mirabamide peptide lacking a 2,3-diaminobutanoic acid residue (Plaza et al., 2007). Interestingly, although such differences in the constitution of unusual AA residues do not deeply interfere with the overall structural profile of these peptides, they greatly affect their anti-viral effects. Additionally, divergent anti-viral effects have also been correlated with peptide cyclization, as is the case of koshikamides, which are non-active in their linear form (Plaza et al., 2010). This same correlation was observed when testing linear and cyclic koshikamides against fungi, including C. albicans (Plaza et al., 2010).

The marine sponge Theonella swinhoei has been studied since the 1990s as a source of different active peptides such as motuporins (De Silva et al., 1992), theonellapeptolides (Figure 4) (Kobayashi et al., 1994), theonegramides (Bewley and Faulkner, 1994; Giordano et al., 2018), cyclolithistide A (Clark et al., 1998) and polytheonamides (Hamada et al., 1994, 2005). One of these compounds, the bicyclic peptide theonellamide F (Figure 4), demonstrated antifungal activity against Aspergillus sp., Candida sp., and Trichophyton sp. in concentrations of 3–12 μg/ml (Matsunaga et al., 1989). The mode of action of this peptide is related to the binding of the histidine-alanine bridge present in its structure that binds to 3-β-hydroxisterols, causing damage to the plasma membrane (Nishimura et al., 2010; Giordano et al., 2018). Theonellamide G (Supplementary Table 1), a glycopeptide also isolated from this sponge, demonstrated cytotoxicity when tested against human colon adenocarcinoma cell lines (HCT-16) with an IC₅₀ of 6.0 μM. Besides, it also showed high antifungal activity against the wild strain (ATCC 32354) and the amphotericin-resistant strain (ATCC 90873) of Candida albicans, with an IC₅₀ of 4.5 and 2.0 μM respectively (Youssef et al., 2014).

Structure-activity correlations have also been observed for Porifera-derived peptides with antifungal, antibacterial and anticancer properties (Figure 1). For instance, callyaerins represent Callyspongia aerizusa sponge-derived peptides with cyclic and linear regions in their structures. Among the callyaerins described by Daletos et al. (2015), callyaerin A (Figure 4) and B share most AA residues in their cyclic region (e.g., isoleucine, proline, leucine, valine, and 4-hydroxyproline) and were the most effective variants against Mycobacterium tuberculosis. In particular, the unusual AA 4-hydroxyproline provides more rigidity to the cyclic ring in these peptides, which has been correlated with possible selective protein binding. Moreover, the differences in the overall hydrophobicity in the linear region between those peptides indicate that callyaerin B is more cytotoxic than callyrarin B (Daletos et al., 2015). Callyaerins A–F and H were assessed against the HeLa (human cervical carcinoma), PC12 (rat brain tumor), and tumor cell line L5178Y (mouse lymphoma), in which callyaerin E was the most active and callyaerin F was the least active (Ibrahim et al., 2010; Giordano et al., 2018). Callyaerin B also showed greater cytotoxicity when tested in the THP-1 cell line (acute human monocytic leukemia) or MRC-5 (human fetal pulmonary fibroblast) (Daletos et al., 2015). Similarly, studies with halycilindramide (Figure 4) have shown that the presence of a macrocyclic lactone ring is required for the antifungal and cytotoxic properties of these peptides (Li et al., 1995). One year later, the identification of halycilindramide E was demonstrated and, instead of presenting a macrocyclic lactone ring at the N-terminus region, it revealed a truncated linear structure with amidated C-terminus. Interestingly, this structural profile resulted in the dissociation of antifungal and cytotoxic activities in halycilindramide E (Li et al., 1996).

Cytotoxic effects have also been reported for marine peptides toward cancer cell lines. Proline-rich cyclic peptides from sponges, including euryjanicin A, carteritins, phakellistatin, and hymenamides, are known to compromise the viability of the human colon cancer cell line (HCT116), human hepatoma (BEL-7402), human lung carcinoma cells (A-549) and HeLA cancer cells (Li Y. et al., 2018; Anand et al., 2019). In general, these peptides present constrained cyclic scaffolds with L-AAs, D-AAs and unnatural AAs in their composition. Interestingly, studies describing the total chemical synthesis of these proline-rich cyclic peptides, although proving their structural and chemical equivalence with their natural counterparts, have shown reduced anticancer effects (Li Y. et al., 2018). This has been attributed to a possible preference of these peptides for a natural, impure condition in which to exert their full activities (Li Y. et al., 2018).

In a study carried out by Tran et al. (2014), four new peptides with antiproliferative and cytotoxic activity were isolated and characterized from Pipestela candelabra, and named milnamides E-G and hemiasterlin D. Another eight known peptides were tested, all isolated from this sponge. These peptides include milnamide A-D (Chevallier et al., 2003; Sonnenschein et al., 2004), hemiasterlin A (Gamble et al., 1999), and geodiamolide D-F (Coleman et al., 1999). All the peptides proved to be efficient against the proliferation of human prostate cancer cells (PC3), and they showed selectivity among cancer cells and human neonatal foreskin fibroblast non-cancer cells (NFF). The results showed that milnamide A and milnamides E–G exhibited greater activity, with IC₅₀ = 11.0 nM (Supplementary Table 1).

Phakellistatins are a group of cycloheptapeptides isolated from sponges of the genus Phakellia. These peptides have been studied for the past two decades due to their strong cytotoxic activity against murine leukemia cells (Meli et al., 2017). The study carried out by Wu et al. (2019) isolated four new cycloheptapeptides from Phakellia fusca. Fuscasins A–D are composed of seven AA residues, including at least one proline residue as well as phakellistatin (Figure 4) family peptides. These four peptides were tested against six human cancer cell lines, but only fuscasin A showed cytotoxic activity against the human cancer cell line HepG2, and it did not show cytotoxicity against non-malignant cells. This result suggests that fuscasin A has the potential to be a targeted antitumor drug.

Compounds isolated from marine sponges were also studied due to their anti-inflammatory activity (Figure 1). This is the case of characellides A and B isolated from Characella pachastrelloides. These peptides are composed of a central tripeptide attached to an alkyl chain ending with a 2,3-dimethyltetrahydropyran and a rare sugar unit. The ability to reduce the production of reactive oxygen species (ROS) in inflammatory conditions by characellides A and B was assessed in microglia BV-2 cells stimulated with lipopolysaccharide (LPS). The microglia-mediated inflammatory process is known for instigating oxidative damage through ROS release. The difference between antioxidant cellular defenses and the production of ROS results in oxidative damage and, consequently, in inflammation. The results showed a 50% reduction in ROS production in the microglia BV-2 cell line stimulated with LPS when treated with characellides (Afoullouss et al., 2019).

A Stylissa massa proline-rich peptide, named stylissatin A (SA), containing both cis- and trans-proline residues in its structure (Kita et al., 2013) showed anti-inflammatory activities in LPS-stimulated murine RAW264.7 macrophages through the inhibitory effects on nitrogen oxide (NO production) (Zhang et al., 2019). This peptide was also assessed for potential inhibition of pre-adipocyte differentiation in Murine 3T3-L1 fibroblasts. Another 23 synthetic SA derivatives were evaluated, and the results showed that SA and its derivatives have potent anti-inflammatory action and inhibit the differentiation of preadipocytes, with the D-Tyr¹-tBuSA (EC₅₀ = 12 μM) derivative being six times more potent than SA (EC₅₀ = 73 μM) (Supplementary Table 1). Moreover, diverse stylissatin A has been reported presenting a macrocyclic scaffold, but with key AA substitutions, including the use of D-tyrosine, D-phenylalanine, D-proline, and D-allo-isoleucine (Zhang et al., 2019). D-AAs were submitted to different chemical modifications, including the addition of tert-butyl ether (tBu), propargyl, methyl, and benzyl ethers and D-glucosyl. In terms of structural profile, these modifications revealed that the macrocyclic scaffolds containing L- and D-AAs differ in their conformations and hydrogen bond patterns, thus influencing their anti-inflammatory effects (Zhang et al., 2019).

In addition, peptides isolated from organisms of the phylum Porifera may also have antifouling activity. This is the case of the compounds barettin and 8,9-dihydrobarettin, isolated from the marine sponge Geodia barretti. These cyclic dipeptides were tested for antifouling activity against Balanus improvisus barn larvae, and they were shown to be compatible with the currently used antifouling agents, with EC₅₀ values of 0.9 and 7.9 μM, respectively, but have the advantage of being non-toxic, unlike the compounds already in use (Sjögren et al., 2004, 2006). The compounds barrettides A (Figure 4) and B, also isolated from G. barretti, are disulfide-containing peptides of amphipathic and hydrophobic nature. Both proved to be efficient in terms of antifouling activity for B. improvisus larvae, with EC₅₀ of 0.6 and 6 μM, respectively (Carstens et al., 2015).

Organisms such as anemones, jellyfish, and corals make up a numerous, diverse, and ecologically important group of marine invertebrates, the phylum Cnidaria, which houses more than 13,000 described species (Turk and Kem, 2009). The cnidarians have radial symmetry, formed by two layers of cells, the ectoderm and the endoderm, separated by a non-cellular matrix, the mesoglea. These organisms have already been extensively studied for their capacity to produce toxins and poisons (Turk and Kem, 2009), but recent research shows that they are capable of producing interesting active molecules, with more than 3,000 products described as starting from this phylum (Daly et al., 2007).

Peptides isolated from invertebrate marine organisms from the phyla Cnidaria, Mollusca, Annelida, Arthropoda, and Echinodermata have also shown antimicrobial properties, mainly against bacteria (Figure 1). Interestingly, as observed for bioactive peptides from the phylum Porifera, constrained structural profiles are commonly found in those organisms. For instance, the antibacterial peptide aurelin (Figure 5) from marine cnidarian Aurelia aurita consists of a defensin-like peptide with six cysteine residues forming three disulfide bonds, and also presenting an unusual link for structure stabilization involving cysteine, aspartic acid, and lysine residues (Ovchinnikova et al., 2006). A study carried out with arelin showed antimicrobial activity against Gram-positive bacteria [Listeria monocytogenes, with minimum inhibitory concentration (MIC) 22.6 μg/ml] and Gram-negative bacteria (Escherichia coli, strain ML-35p, MIC 7.6 μg/ml) (Ovchinnikova et al., 2006). The set of six cysteines present in this peptide forms a domain identified in other proteins isolated from vertebrates and invertebrates. Although the function of this domain is not so clear, it is estimated that it acts as an extracellular ligand or as a toxin, blocking the K + channel (Ovchinnikova et al., 2006; Shenkarev et al., 2012). Similarly, two mollusk-derived peptides, named mytichitin-CB and RpdefB, are also effective in countering bacterial growth, which has been attributed to their constrained defensin-like structures (Novoa et al., 2016; Yang et al., 2018). This cysteine-rich structure profile has also been demonstrated for peptides from the phylum Echinodermata, including the peptide PpCrAMP (Kim et al., 2018).

In research carried out by Lima et al. (2013), a screening of six cnidarians (Carijoa riisei, Muriceopsis sulphurea, Neospongodes atlantica, P. caribeorum, Plexaurella grandiflora, and Phyllogorgia dilatata) was carried out. The crude extract of these cnidarians showed inhibition that varied from 33 to 94% against the bacteria that cause hospital infections Staphylococcus aureus, Proteus mirabilis, Klebsiella pneumoniae, Shigella flexneri, E. coli, Streptococcus pyogenes, and Salmonella typhimurium. From the P. dilatata extract, the peptide Pd-AMP1 was extracted and purified, which presented the best result against S. aureus (Supplementary Table 1).

Many antitumor peptides have been isolated from cnidarians (Figure 1). The Anthopleura anjunae antitumor peptide (AAP-H) was obtained by enzymatic hydrolysis of the alkaline protease of the sea anemone Anthopleura anjunae. It is a pentapeptide with an AA sequence of Tyr-Val-Pro-Gly-Pr. This peptide was investigated for inhibitory effects on the proliferation of DU-145 cells in prostate cancer, and it showed antiproliferative activity (with an IC₅₀ concentration of 9.6, 7.9, and 2.3 mM in 24, 48, and 72 h, respectively), inducing apoptosis, causing a decrease in cancer cell growth, and reduced the percentage of viable cells. It also caused morphological changes in DU-145 cells for DNA fragmentation, the formation of bubbles in the membrane and cell shrinkage (Wu et al., 2018). Another study showed that the antitumor mechanism of this peptide in prostate cancer cells may involve the regulation of the PI3K/AKT/mTOR signaling pathway and had no toxic effects for normal fibroblasts. Thus, AAP-H is a promising anti-prostate cancer agent and can be studied as a functional food for the prevention or treatment of this cancer type (Li X. et al., 2018). Three peptides isolated from the coral Sarcophyton glaucum also presented anticancer activity. The peptides AERQ, RDTQ and AGAPGG exhibited cytotoxicity against the human cervical cancer (HeLa) cell line, with EC₅₀ values of 4.9, 5.6, and 8.6 mmol/L, respectively. These compounds manifested low cytotoxicity on non-cancerous Hek293 cells (Supplementary Table 1). Besides that, AERQ, RDTQ and AGAPGG have cytotoxic activity that is 5.8, 5.1, and 3.3 times stronger than that of the anticancer drug 5-fluorouracil, respectively (Quah et al., 2019).

The phylum Mollusca is composed of aquatic invertebrate organisms, such as mussel, octopus, squid, and oyster, and terrestrial organisms, such as snail (Otero-Gonzáiez et al., 2010; Zhong et al., 2013). Among the known defense mechanisms, these organisms use only physical barriers and the innate immune system as a way of protecting against the most diverse pathogens, since they do not have adaptive immunity mechanisms (Zhong et al., 2013). Organisms in this phylum produce peptides that have different functions, and peptides isolated from different tissues of these organisms are found in the literature (Supplementary Table 1).

Conopeptides or conotoxins belong to the family of peptides isolated from the poison produced by snails from the Conus genus, such as the peptide Lo1A (Figure 5) isolated from Conus longurionis. These are characterized by having a small size and having a composition rich in cysteine, in addition to presenting a unique characteristic because they are highly selective and potent ligands to diverse receptors and ion channels (Lebbe et al., 2014, 2016). The first peptide approved for commercial use was a conopeptide/conotoxin called ω-MVIIA (Bowersox and Luther, 1998; Figure 5), derived from the venom of a fish-hunting cone snail Conus magus, with potent analgesic properties (Rigo et al., 2013). Since then, many peptides with different biological activities have reached different stages of development in the pipeline for the market (Jimeno et al., 2004; Blunt et al., 2018).

Several AMPs have already been isolated and characterized as produced by organisms of this phylum, most abundantly in mussels (Figure 1). The mussel Mytilus coruscus has been the subject of studies for several years, which led to the isolation of AMPs myticusin-1, mytichitin-CB and myticusin-beta. Myticusin-1 is a cysteine-rich peptide with an unusual pattern of the AA. It presented antimicrobial action against Gram-positive bacteria, such as S. aureus (MIC < 5 mM), and Gram-negative, such as E. coli (MIC > 10 mM) (Liao et al., 2013). Mytichitin-CB was isolated from the hemolymph of this mollusk; it is formed by 55 AA residues, with three disulfide bonds. Like myticusin-1, this other peptide has greater antimicrobial activity against Gram-positive bacteria, in addition to antifungal activity, both of which were demonstrated in tests against Bacillus subtilis, S. aureus, Sarcina luteus, and Bacillus megaterium (MIC < 5 mM) and against the fungi C. albicans and Monilia albicans (MIC 6.2–25 mM) (Qin et al., 2014; Oh et al., 2018). Myticusin-beta has an N-terminal sequence similar to myticusin-1, which begins composed of a signal peptide (24 AA residues) and a mature peptide (104 AA residues). This peptide also showed antimicrobial activity against Gram-positive and Gram-negative bacteria, while its recombinant peptides have shown anti-parasitic activity against scuticociliates (Oh et al., 2020). The search for new AMPs in the genome and transcriptome and peptide-derived synthesis is becoming increasingly popular, given the difficulty in extracting peptides naturally produced by organisms. Therefore, genome analysis paves the way for the production of new multifunctional peptides. Octominin, for example, was detected from the analysis of the Octopus minor transcriptome, being modified and synthesized based on the defense protein 3 cDNA sequence from the mollusk. Experimental data demonstrated that this peptide inhibited the growth of C. albicans with minimum fungicidal concentration of 200 μg/mL and (MIC = 50 μg/mL) and a rapid decrease in the number of viable cells (35 and 5% cell viability at 24 h, in treatment with 50 and 100 μg/mL of octominin, respectively). The mechanism of action of octominin is related to the formation of pores in the cell wall and membrane and the accumulation of ROS (Nikapitiya et al., 2020). It also presents anti-inflammatory activity in LPS-activated macrophages by inhibition of pro-inflammatory factors, like cytokines, NO and chemokines (Supplementary Table 1; Sanjeewa et al., 2020).

Some studies on AMP isolation have sought to demonstrate the activity of these compounds against groups of bacteria that affect the health of other marine organisms important to the fishing economy, such as crustaceans, fish, and mollusks (Austin and Zhang, 2006; Liu et al., 2013). This is the case of the peptides RpdefB and VpMacin. RpdefB, identified as being of the defensin type, has been isolated from Ruditapes philippinarum and expressed in the five different tissues of the mollusk. This peptide showed high antibacterial activity against Gram-negative and Gram-positive bacteria, with MIC ranging between 0.5 μM (Vibrio splendidus) and 8.0 μM (S. aureus). RpdefB provided an increase in membrane permeability in an experiment carried out with E. coli, resulting in the death of this microorganism (Yang et al., 2018). VpMacin, a peptide characterized as belonging to the macin family, was isolated from different tissues of Venerupis philippinarum. The recombinant peptide, called rVpMacin, was tested against different bacteria, showing activity against human pathogenic strains and greater activity against strains that are pathogens of marine organisms, such as Vibrio alginolyticus, Vibrio harveyi, and V. splendidus (MIC between 0.5 and 4.0 μM) (Yang et al., 2019).

Sepia ink from mollusks has been known and used for thousands of years in Chinese medicine. It has many properties, such as anti-hypertensive, antibacterial, anti-retrovirus, antioxidant, and antitumor activities. However, the first study to demonstrate the induction of apoptosis in cancer cells of a sepia ink peptide was only published in 2017. The polypeptide SHP was isolated via the hydrolysis of sepia ink from Sepia esculenta and was subjected to a cell proliferation assay on prostate cancer cell line PC-3 (Pca PC-3). The results indicated that SHP inhibited the proliferation of Pca PC-3 in a time- and concentration-dependent (5, 10, 15, 20 mg/ml treated with SHP for 24, 48, and 72 h) and induced apoptosis by upregulation of the Bcl-2/Bax ratio (Huang et al., 2017).

Interestingly, some peptides initially isolated from marine invertebrates can be produced by other organisms (Faircloth and Cuevas, 2006). This is the case of the peptides kahalalides. These peptides were isolated from mollusks Spisula polynyma and Elysia rufescens and they have antitumor action (Gracia et al., 2006; Rao et al., 2008). However, a study by Zan et al. (2019) showed that a bacterial symbiont Candidatus Endobryopsis kahalalidefaciens produced kahalalide (Figure 5) for the chemical defense of the host (alga Bryopsis sp.). Subsequently, this peptide is removed by the mollusk from its food and used for defense.

The peptides mytilin B (Figure 5) and myticin C were isolated from the mussel Mytilus galloprovincialis, with myticin C being the first antiviral peptide against mollusk pathogens. In a study carried out by Novoa et al. (2016), oyster resistance to herpesvirus Ostreide 1 was demonstrated, when mussel hemolymph was introduced during the incubation period of oyster hemocytes, with myticin C the main peptide found in both. Modified myticin C peptides also showed antiviral activity with human herpes simplex viruses 1 and 2, raising the proposal to use it for veterinary and medicinal use (Balseiro et al., 2011).

Photo-protective peptides were also found in mollusk tissues. Peptides from the oyster Crassostrea hongkongensis (OPs) were obtained from the protein hydrolysates and the photo-protective effects investigated by topical application on mouse skin. OPs contained 24 peptide chains (formatted by 4-17 AA) that showed antioxidant activity, inhibiting metalloproteinase secretion and malondialdehyde production. Moreover, topical OP application demonstrated anti-inflammatory activity caused by decreased production of inflammatory cytokines. These results indicate that OPs are photo-protective peptides and can be used as cosmetic or therapeutic products against photoaging (Peng et al., 2020).

Organisms of the phylum Annelida inhabit terrestrial, freshwater, and marine environments and are classified in the classes Polychaeta and Clitellata. The organisms of this phylum have a segmented body with bilateral symmetry, with worms and leeches as the best-known organisms. The Polychaeta class is the largest group, comprising about 14,000 species and most of the diversity within that phylum. They are invertebrates found in almost all marine environments (de Paiva, 2006; Coutinho et al., 2017). Despite the large number of species in this phylum, studies are still few and restricted to a few species. Much of the research is on earthworms (oligochaetes), due to their biological role in the soil, and some species of polychaetes (Schenk and Hoeger, 2020).

Marine polychaetes excel in isolating AMPs (Figure 1). As in other phyla, structural restrictions have also been observed in antibacterial and antifungal peptides from the phylum Annelida, which present structures organized in dimeric β-hairpins, double-stranded antiparallel beta-sheet and α-helix stabilized by disulfide bonds (Kaas et al., 2010; Panteleev et al., 2018), such as the peptide alvinellacin (Figure 5; Lie Tasiemski et al., 2014). The AMPs arenicin-1, 2, and 3 were extracted and purified from the marine polychaete Arenicola marina, both formed by 21 AA residues. The peptides showed antimicrobial activity against Gram-positive and Gram-negative bacteria (S. aureus, Enterococcus faecium, S. epidermidis, E. coli, Pseudomonas aeruginosa, and Listeria monocytogenes), as well as against the fungus C. albicans (Park and Lee, 2009), inhibiting growth in concentrations greater than 25 μg/ml (Ovchinnikova et al., 2004; Lee et al., 2007; Wang et al., 2014b). A study by Andrä et al. (2008) showed that arenicin-1 has potent antimicrobial activity against mutant strains of P. mirabilis resistant to polymyxin B (Supplementary Table 1). The mechanism of action of arenicin 1 and 2 is related to its structure and destabilization of the bacterial plasma membrane (Lee et al., 2007; Cho and Lee, 2011). These factors were studied by Shenkarev et al. (2011). The peptide arenicin-2 has a dimeric β-hairpin hook structure and produces pores in the cell membrane. A recent study proposed several variants of arenicin-1 to assess the role of its structure and symmetry. The results showed that the arrangement of the arenicin-1 β-hairpin (Figure 5) caused an increase in antimicrobial activity against Gram-negative bacteria but a decrease against Gram-negative (Orlov et al., 2019).

Partially cyclic peptides from the phylum Annelida also present anticancer properties, as is the case of nicomicin-1 (Figure 5). This peptide presents a structural arrangement that resembles the Rana-box motif observed in α-helical peptides found in frog skin. It consists of an N-terminus amphipathic α-helix, along with a six-residue loop in a cyclic arrangement and stabilized by a disulfide bond, which has been correlated with this peptide’s antibacterial and anticancer activities. The peptide nicomicin-1 has a unique structure when compared to AMPs isolated from other polychaetes, due to these characteristics. This AMP was isolated from Nicomache minor (Panteleev et al., 2018) and had a BRICHOS domain as a precursor, characterized by participating in post-translational protein processing (Chen et al., 2017). Nicomicin -1 showed activity against Gram-positive bacteria (M. luteus, B. subtilis, Bacillus licheniformis, S. aureus 209P, S. aureus ATCC 29213, Rhodococcus sp.), with MIC varying between 0.062 and 2 μM. The cytotoxicity of nicomycin-1 for cervical adenocarcinoma cells was dose-dependent and reached a percentage of 85% of dead cells in concentrations of 32 μM of the peptide (Panteleev et al., 2018). In the most recent study about AMPs from polychaetes, a new recombinant analog peptide was produced from Capitella teleta. Capitellacin (Figure 5) has a β-hairpin structure, a BRICHOS domain and high homology with the tachyplesins (Figure 5) AMP family. Analysis of the antimicrobial activity of capitellacin demonstrated that this peptide has broad-spectrum activity, but it was up to eightfold lower than that of tachyplesin-1 (a peptide from the tachyplesins family). Unlike other peptides with β-hairpin structure, capithelinacin was inefficient in breaking the cytoplasmic membrane and inhibiting bacterial translation, suggesting other mechanisms of action and targets (Panteleev et al., 2020).

Another much-studied polychaete is Perinereis aibuhitensis. The peptide perinerin was extracted from this organism, a hydrophobic peptide composed of 51 AA residues. This peptide showed antimicrobial activity against the fungus Paecilomyces heliothis (MIC 25 μg/ml), high activity against P. aeruginosa, B. megaterium, and Aerococcus viridans (MIC < 15 μg/ml), moderate activity against E. coli K-12, S. aureus and M. luteus, and lower activity against Proteus vulgaris (MIC > 50 μg/ml) (Pan et al., 2004). Peptides present in protein extracts of Perinereis aibuhitensis also showed antithrombotic (Li et al., 2017) and antihypertensive activities (Chen and Wang, 2017). Jia et al. (2017) isolated the peptide P. aibuhitensis (PAP), a decapeptide with anticancer action that was tested by Jiang et al. (2019) against human lung cancer H1299 cells cultured in vitro, where this peptide showed potential inhibition of malignant lung cancer cell growth and tumor cell apoptosis. This study suggests that PAP could be used for the prevention or treatment of human non-small-cell lung cancer in the future.

A study by Park et al. (2020) isolated and evaluated the peptide NCW from the worm Marphysa sanguinea. NCW was evaluated for anti-inflammatory and antioxidant effects and its cytotoxicity in Raw264.7 cells induced by LPS. The results showed that NCW has a high elimination capacity of 2,2-diphenyl-1-picrilhidrazil (DPPH) when compared to vitamin C (IC₅₀ of 17.5 μg/ml and 2.7 μg/ml, respectively). It also had an anti-inflammatory effect by decreasing NO production stimulated by LPS and inhibiting the secretion of pro-inflammatory cytokines IL-1β and TNF-α, in addition to NCW not showing cytotoxicity in Raw264.7 cells induced by LPS (Supplementary Table 1).

When stimulating the mud crab with LPS, Anju et al. (2019) increased the mRNA expression of the Scylla serrata hemocytes and increased the production of the peptide Ss-arasin. Ss-arasin is formed by 65 AAs with a predicted molecular weight of 7 kDa, and it was expressed in a prokaryotic heterologous system. Recombinant rSs-arasin showed significant activity against S. aureus, P. aeruginosa, and E. coli. This recombinant peptide also inhibited the growth of human cervical carcinoma (HeLa) and colon carcinoma (HT-29) cells. These discoveries are of the utmost importance for structure-activity relationships, in order to optimize biological functions for future drug development.

Membrane peptides can be classified as cell-penetrating peptides and AMPs, recognized for playing interchangeable roles. Tachipesin is a peptide isolated from the hemolymph of the horseshoe crab (Tachypleus tridentatus), known for having antimicrobial properties, and investigated for its ability to penetrate cells. Derived from a marine organism, it has internalized cell penetration, being found in plant and mammalian systems. It was established as an efficient non-viral macromolecule nanocarrier (Jain et al., 2015).

Anti-lipopolysaccharides (ALFs) are factors known as important defense molecules for the host of crustaceans. Containing a LPS-binding domain (LBD), some ALFs have strong antimicrobial activity. Zhou et al. (2019) described a group G ALF of the Giant Tiger Shrimp (Penaeus monodon) (ALFPm11). It is a highly amphipathic peptide, with five positively charged residues separated by aromatic residues, normally expressed abundantly in the hepatopancreas of P. monodon. Chemically synthesized ALFPm11-LBD exhibited high inhibitory activity against various bacteria, for example Exiguobacterium sp., Bacillus sp., and Acinetobacter sp., thereby efficiently inducing the agglutination of Gram-positive and Gram-negative bacteria and causing significant permeabilization of the bacterial membrane. Thus, an effective new ALF has been described in P. monodon, demonstrating its antimicrobial mechanism, suggesting potential applications for the future.

Histone H2A participates in the host’s immune defense through the generation of special AMPs in vertebrates and invertebrates. Although thousands of AMPs have been reported in various species, AMPs in crabs are better known (Figure 1). Chen et al. (2015) determined the existence of the peptide sphistin with 38 AA residues and antimicrobial activity based on the analysis of the sequence of an H2A histone identified from Scylla paramamosain. Sphistin exerted high antimicrobial activity against Gram-positive, Gram-negative bacteria and yeasts, including Aeromonas hydrophila, Pseudomonas fluorescens, and Pseudomonas stutzeri, important aquatic pathogens. In the bacterial cells treated with sphistin, leakage of the cell content and rupture of the cell surface were observed. It has been proven that the increased permeability of the E. coli cytoplasmic membrane was caused by sphistin. Synthetic sphistin did not exhibit cytotoxicity to cultured crab hemolymph and mammalian cells, even at a high concentration. This is the first report of a histone-derived sphistin identified from S. paramamosain, which can be promising for application in aquaculture and veterinary medicine (Chen et al., 2015).

An AMP similar to the crustin of giant tiger prawn hemocytes, P. monodon, was partially characterized at the molecular level, and the phylogenetic analysis was performed by Antony et al. (2011). The 299 bp partial coding sequence and 91 deduced AA residues had conserved cysteine residues characteristic of shrimp crustins. The phylogenetic tree and the sequence comparison clearly confirmed the divergence of this crustin-like AMP from other shrimp crustins. The differential expression of a crustin-like AMP in P. monodon in response to the administration of several immunostimulants, namely, two marine yeasts (Candida haemulonii S27 and Candida sake S165) and two β-glucan isolates (extracted from C. haemulonii S27 and C. sake S165), were noted during the study. Responses to the application of two gram-positive probiotic bacteria and Micrococcus were also observed. The immunological profile was recorded pre- and post-challenge with the white spot syndrome virus (WSSV) by semiquantitative RT-PCR. Expressions of seven WSSV genes were also observed to study the intensity of viral infection in experimental organism. A crustin-like AMP has been found to be expressed constitutively in the organism and significant negative regulation can be observed after the WSSV challenge. Notable negative regulation of the gene was observed in organisms fed a pre-challenge immunostimulant followed by a post-challenge WSSV of significant positive regulation. The tissue expression of a crustin-like AMP in the administration of C. haemulonii and Bacillus showed maximum transcriptions in the gills and in the intestine. Marine yeast, C. haemulonii and probiotic bacteria, Bacillus, increased the production of an AMP similar to crustin and conferred significant protection on P. monodon against WSSV infection (Antony et al., 2011).

Antimicrobial peptides studied from hematocyte strata of the red king crab, Paralithodes camtschaticus, are described by Moe et al. (2018). The peptides were isolated by bioassay purification, showing that they are cationic peptides rich in cysteine (Cys), called paralithocins 1–3. The peptides (38–51 AAs in length) share a single Cys motif consisting of eight Cys, forming four disulfide bridges with a Cys1–Cys8 (Cys relative position) connectivity, Cys2–Cys6, Cys3–Cys5, and Cys4–Cys7, a disulfide arrangement that has not been previously reported among AMPs. These peptides are responsible for inhibiting the growth of several marine bacterial strains with minimal inhibitory concentrations in the range of 12.5–100 μM. These findings confirm the hypothesis that marine organisms are a valuable source for the discovery of bioactive peptides with new structural motifs.

With the recent spread of obesity in developing countries, more attention is focused on the development of appetite-moderating drugs with low side effects. Anti-obesity peptides generally control satiety hormonally. Two important synthetic anti-obesity peptides already characterized are cholecystokinin and gastrin, appetite suppressants with multiple cellular targets (Cheung et al., 2015). Some already characterized marine anti-obesity peptides stimulate the synthesis of cholecystokinin – such as peptides from shrimp head protein hydrolysates, which can stimulate cholecystokinin release in STC-1 cells – or are structurally and mechanistically similar to gastrin/cholecystokin (Sable et al., 2017). The shrimp anti-lipopolysaccharide factor (SALF) was described by Wang L. et al. (2017), an AMP from black tiger prawns that increases the anticancer activity of cisplatin in vitro and inhibits the growth of HeLa cells in nude mice. These peptides also exhibit anti-cancer activity defined in cancer cell lines of cancer and human liver, even when removed from shrimp residue (Wang L. et al., 2017).

Echinoderms are marine invertebrates, phylogenetically related to chordates and hemichordates. They have a unique morphology that includes pentameric radial symmetry in their adult forms and bilateral symmetry in larvae and a vascular water system. Echinoderms live in diverse marine environments, rich in fungi, bacteria, viruses and many pathogenic organisms of echinoderms. Thus, these organisms evolved in a complex way, and their immune system is totally innate but highly effective and sophisticated. The complexity of the echinoderm’s immune system can be understood by looking at the large number of AMPs isolated from these organisms (Figure 1).

The first AMP reported from the sea star was the cysteine-rich peptide named PpCrAMP from Patiria pectinifera. It is formed by 38 AA residues with two disulfide bonds and C-terminal amination with a glycine. Synthetic PpCrAMP showed antimicrobial activity against Gram-negative bacteria, S. enterica and Shigella flexneri (MEC of 4.5–31.4 μg/ml), and Gram-positive bacteria, B. subtilis, S. aureus and M. luteus (MEC of 15.6 to >250 μg/ml). The coelomic epithelium extract was also tested and activity against E. coli was detected (Kim et al., 2018).

Strongylocins were the first peptides from echinoderms whose genes were completely sequenced. SdStrongylocin 1 is formed by 48 AA residues while SdStrongylocin 2 has 51 AA residues; both have strong activity against Gram-positive and Gran-negative bacteria (MIC of 1.3–2.5 μM). These peptides were extracted from Strongylocentrotus droebachiensis and were characterized as rich cysteine peptides (Li et al., 2015). From the coelomocytes from S. droebachiensis, the peptides centrocin 1 and 2 were also extracted. These molecules are heterodimeric peptides formed by a chain with 30 AAs (heavy chain) and a chain with 12 AAs (light chain). The heavy chain is linked to the activity against Gram-positive and Gram-negative bacteria (MIC of 1.3–2.5 μM) while the light chain did not show activity or influence in the antimicrobial activity of the heavy chain (Li et al., 2010, 2015).

Three AMPs were isolated and characterized from the coelomic fluid of the sea urchin Echinus esculentus. Two of these peptides are heterodimeric, EeCentrocin 1 and 2, and the other is a cysteine-rich peptide, EeStrongylocin 2. EeCentrocin 1 demonstrated potent antimicrobial activity against Corynebacterium glutamicum and S. aureus (MIC = 0.78 μM against both) and E. coli and P. aeruginosa (MIC = 0.1 and 0.78 μM respectively) (Supplementary Table 1). The other two peptides could not be tested in isolation due to the difficulty of purification, but the mix of these peptides also demonstrated antimicrobial activity (Solstad et al., 2016). Another study made modifications in the structure of EeCentrocin 1 to produce a shorter drug peptide using its heavy chain. The new peptide named P6 was formed of 12 original AA residues of the N-terminal from EeCentrocin 1, two modifications of the AA and one C-terminal amidation. P6 showed greater antibacterial and antifungal activity than EeCentrocin 1, in addition to presenting lower hemolytic activity and no cytotoxic activity (Solstad et al., 2020).

Several peptides with inhibitory natural angiotensin-converting enzyme (ACE) activity have been isolated from diverse marine organisms. These peptides can be used as antihypertensive drugs. Peptides NVA and NLG with ACE inhibitory action were extracted from Acaudina molpadioidea protein hydrolysates, present in the body wall of this sea cucumber (Zhu et al., 2011; Shen et al., 2014). They were modified with the addition of exogenous proline, increasing the inactivation of ACE, with IC₅₀ values of 8.2 ± 0.2 μM for PNVA and 13.2 ± 0.4 μM for PNLG (Li J. et al., 2018). Compounds with this mechanism of action have been studied as a possible treatment for diseases that present hypertension, as is the case of COVID19. SARS-CoV-2 enters cells via interactions between the Angiotensin-converting enzyme 2 (ACE2) and the Spike viral protein. Marine peptides with antiviral and anti-ACE2 activity can be an alternative tool in solving this problem (Festa et al., 2020). From this echinoderm, four peptides (Fa.2-A, Fa.2-B, Fa.2-C, and Fa.2-D) were also isolated from the hydrolysis of collagen. The peptide Fa.2-C showed the highest scavenging activity for 2,2-diphenyl-1-picrylhydrazyl (DPPH) at a concentration of 0.2 mg/mL (Supplementary Table 1). This indicates a reduction in oxidative damage by converting the DPPH radical to less harmful substances. Thus, it can be considered a promising antioxidant collagen peptide and used in the food and drug industry (Jin et al., 2019).

Studies indicate that peptides with chelating action can be used in the production of human food supplements. This is the case of the zinc chelating peptide (ZCP), isolated from the edible sea cucumber Stichopus japonicas. ZCP is composed of eight AA residues (WLTPTYPE) and has a molecular weight of 1005.5 Da, with a zinc chelating capacity equal to 33.3%. Researchers point out that future work can better analyze the mechanism of action of ZCP and the effects regarding the intensification of intestinal zinc absorption (Liu et al., 2019a, b). This sea cucumber was also studied for its capacity to release antidiabetic peptides. The study involved simulating digestion processes by in vitro model, where 58 peptides with lower molecular weight (<3 KDa) were found and characterized. These peptides showed the highest inhibitory activity of the enzyme dipeptidyl peptidase IV (DPP-IV) when compared to anagliptin, a DPP-IV inhibitor. This indicates that S. japonicas can be used to release antidiabetic peptides in gastrointestinal digestion as a functional food (Gong et al., 2020).

The small-molecule oligopeptides (SOP) isolated from the sea cucumber Codonopsis pilosula were studied for their potential immuno-modulatory effects. The assays performed with mice showed that these molecules appeared to increase innate and adaptive immune responses when SOPs were orally administered. This response occurs by NK cell action, macrophage phagocytosis, and humoral and cell-mediated immunity (Supplementary Table 1). Thus, these oligopeptides could be used for cancer patients and immunocompromised persons, to increase immune functions (He et al., 2016). In another study, the SOP isolated from sea cucumber showed healing activity in wounds in diabetic mice. This action can be explained by the capacity for increased angiogenesis, synthesis, and deposition of collagen, which enhanced the antioxidant levels and reduced the inflammatory response (Li D. et al., 2018).

Compared to other phyla, it is worth noting that, when studying bioactive peptides from Chordata phylum organisms (vertebrates), a very different picture is observed. Marine peptides isolated from these organisms are usually composed only of natural AAs in a linear structure that transits from random coil to α-helix and beta-sheet when in contact with bacterial and fungi surfaces. Among the peptides from Chordata are piscidins and marine cathelicidins (Broekman et al., 2011; Mihailescu et al., 2019).

Piscidin (Figure 5) pools are important components of the innate (non-specific) immune system in fish, and they have potent and broad-spectrum antimicrobial and antiparasitic activities (Figure 1). A new antimicrobial cationic peptide from Pseudosciaena crocea is described by Niu et al. (2013), which exhibits a genomic organization (three exons and two introns) and propeptide (signal peptide, mature peptide, and prodomain), conserved signal peptide (22 AAs) and ratio for consensus I-X5-H-X4-IH. In fish piscidins, Pc-pis demonstrated a relatively low general conservation with other known piscidins, which was obviously incorporated in the AA composition of the peptide. Pc-pis is surprisingly rich in glycine residues (27.3%), which interrupted the amphipathic structure of the peptide. Relative quantitative real-time PCR revealed that Pc-pis is typically expressed by gills. The analysis of the sequence, structural characteristics and tissue distribution suggested that Pc-pis was genetically related to the piscidine family and may be a new AMP similar to piscidine. Quantitative PCR analysis revealed that the expression of Pc-pis in the spleen, head-kidney, liver, intestine, skin and gills can be regulated during infection by Cryptocaryon irritans and after the decrease of C. irritans, implying a role for Pc-pis in the immune defense system against C. irritans and secondary bacterial infections. Pc-pis exhibited broad-spectrum activity against bacteria, fungi and C. irritans in parasitic stages. These results provided evidence of the antiparasitic activity of piscidins against ectoparasites of marine fish, namely C. irritans trophons, and further indicated that these data provided new insights into the innate immunity of P. crocea against external protozoan parasites and microbial infections and facilitate the assessment of Pc-pis as a therapeutic agent against the invasion of pathogens (Niu et al., 2013).

Cathelicidins are a group of AMPs that have antibacterial, antifungal, antiviral, immunostimulatory, and immunomodulatory properties. The cathelicidin family is characterized by a highly conserved N-terminal cathelin domain and a variable C-terminal antimicrobial domain that can be extracted by the action of proteinases. Cathelicidin works together with defensins and high concentrations of cathelicidin are found at sites of inflammation, where they appear to destroy microorganisms and act as a bridge between innate and late immunities. The observation that AMPs are also produced in the epithelium supports the hypothesis that they are part of a type of primary defense system. Cathelicidins are among the best characterized AMPs and play an important role in mammalian innate immunity. A new mature cathelicidin peptide (codCath) was isolated by Broekman et al. (2011) from Atlantic cod and the function of codCath was characterized. The peptide showed sensitivity to salt with an annulment of activity at physiological salt concentrations. In a medium of low ionic strength, it showed activity against marine and non-marine Gram-negative bacteria, weak activity against a Gram-positive bacterium and antifungal activity. CodCath’s actions are rapid death accompanied by pronounced cell lysis. Extracellular products (E) from three marine bacteria caused the peptide to break down into smaller fragments, and the cleaved peptide lost its antibacterial activity. Peptide proteolysis, on the other hand, was abolished by previous heat treatment of ECPs, suggesting protease involvement. No peptide cytotoxicity was observed in fish cells, and the selectivity of activity was confirmed with bacterial and mammalian membrane mimetics. In this way, the potent broad-spectrum activity of codCath suggests a role of the peptide in the immune defense of cod (Broekman et al., 2011).

Another AMP (Salmo salar) – which acts as an activation signal for the marine parasite copepod Lepeophtheirus salmonis. L. salmonis – was exposed to 0, 7, 70, and 700 ppb of Cath-2 (cathelicidin-2) and the neural activity, swimming behavior and gene expression profiles of organisms in response to the peptide were evaluated. The neurophysiological, behavioral and transcriptomic results were consistent: L. salmonis detects Cath-2 as a water-soluble peptide released from the skin of the salmon, triggering the chemosensory sensorineural activity associated with altered swimming behavior of copepodids exposed to the peptide, and genes related to chemosensorials increased in copepodids exposed to the peptide. L. salmonis are activated by Cath-2, indicating a strong link between this peptide and the chemosensory system of the salmon louse (Núñez-Acuña et al., 2018).

Antimicrobial peptides play a defense role against microbial invasion. Liver Expressed Antimicrobial Peptides-2 (LEAP-2) is an AMP that belongs to a group of peptides rich in cysteine. Hwang et al. (2019) identified and characterized the molecular properties of LEAP-2 in sea bream (Diplodus sargus). The expression levels of LEAP-2 (RbLEAP-2) were evaluated in 12 different healthy fish tissues and the expression pattern of RbLEAP-2 after infections by Edwardsiella piscicida, Streptococcus iniae and iridovirus from (RSIV) was observed. These data show that RbLEAP-2 plays an important role in innate immunity when infected with a pathogen.

Marine peptides that are known to induce cell death by DNA fragmentation, nucleic shrinkage and swelling of the cell membrane have been described by Zheng et al. (2011). Didemnins belong to a family of depsipeptides that have antitumor, antiviral and immunosuppressive activities, and they were first isolated from Caribbean marine organism tunicates by Rinehart et al. (1981). Didemnin B, which is a branched N-methylated cyclic peptide, was isolated from the genus Trididemnum, and it has the ability to induce the death of a variety of cells by DNA fragmentation within the cytosol. Further studies showed that didemnins are produced by symbiotic bacteria in tunicates. Didemnins are produced by the marine α-proteobacteria Tistrella bauzanensis and Tistrella mobilis (Tsukimoto et al., 2011). These bacteria synthesize the non-ribosomal peptide synthetase-polyketide synthase enzyme complex responsible for the production of didemnin B precursors (Xu et al., 2012; Zan et al., 2019; Supplementary Table 1).

A derivative of the shark cartilage stratum is described as neovastat (AE-941), a liquid extract with defined standardization comprising a <500 kDa fraction of shark cartilage; this product of the mud shark Squalus acanthias was seen to be a direct inhibitor of the growth of tumor cells and angiogenesis. Mice that were treated with neovastat showed a significant reduction in the inflammatory cell count in BAL liquid, and those mice that were treated with neovastat showed a significant reduction in the expression of VEGF and HIF2 alpha in lung tissue (Zheng et al., 2011).

Styelin D, eusynstyelamide (Figure 5), botrilamides A – D (1–4), lissoclinamides and molamidas were isolated from ascidians, presenting a potential for cytotoxicity, but studies still have not provided precise knowledge about this mechanism. Zheng et al. (2011) described the peptide styelin D, as quite cytotoxic and hemolytic for eukaryotic cells. Isolated from blood cells of ascidia Styela clava, this peptide has antimicrobial activity, with 32 residues C-terminal amidate (Supplementary Table 1). Lissoclinamides are cyclic peptides that have shown significant antineoplastic activity, as well as other pharmacological properties against human fibroblasts and bladder carcinoma cell lines and normal lymphocytes, after being isolated from the aplousobranch Lysoclinum patella. Among them, the most potent is lissoclinamide 7 (Figure 5), containing two thiazoline rings, which rivals didemnin B for in vitro cytotoxicity.