Sea stars are an abundant group of marine invertebrates that display remarkably robust regenerative capabilities throughout all life stages. Numerous proteins and peptides have been identified in a proteome study on the coelomic fluid (biofluid) of the common sea star Asterias rubens, which appear to be involved with the wound-healing response in the organism. However, the three-dimensional structure and function of several of these injury-responsive peptides, including the peptide KASH2, are yet to be investigated. Here, we show that the KASH2 peptide adopts a disulfide-directed beta-hairpin fold (DDH). The DDH motif appears to be evolutionarily related to the inhibitor cystine knot motif, which is one of the most widespread disulfide-rich peptide folds. The DDH motif was originally thought to be restricted to arachnids, but our study suggests that as a result of convergent evolution it could also have originated in sea stars. Although the widely conserved DDH fold has potential cross-phyla wound-healing capacity, we have shown that KASH2 does not enhance the proliferation of human fibroblasts, a simple method for wound-healing re-epithelialisation screening. Therefore, additional research is necessary to determine the role of KASH2 in the sea stars.

Scleractinian corals are crucially important to the health of some of the world's most biodiverse, productive, and economically important marine habitats. Despite this importance, analysis of coral peptidomes is still in its infancy. Here we show that the tentacle extract from the stony coral Heliofungia actiniformis is rich in peptides with diverse and novel structures. We have characterized the sequences and three-dimensional structures of four new peptides, three of which have no known homologues. We show that a 2 kDa peptide, Hact-2, promotes significant cell proliferation on human cells and speculate this peptide may be involved in the remarkable regenerative capacity of corals. We found a 3 kDa peptide, Hact-3, encoded within a fascin-like domain, and homologues of Hact-3 are present in the genomes of other coral species. Two additional peptides, Hact-4 and Hact-SCRiP1, with limited sequence similarity, both contain a beta-defensin-like fold and highlight a structural link with the small cysteine-rich proteins (SCRiP) family of proteins found predominantly in corals. Our results provide a first glimpse into the remarkable and unexplored structural diversity of coral peptides, providing insight into their diversity and putative functions and, given the ancient lineage of corals, potential insight into the evolution of structural motifs.

Venom peptides are promising drug leads, but their therapeutic use is often limited by stability and bioavailability issues. In this study, we designed cyclic analogues of α-conotoxin CIA, a potent muscle nicotinic acetylcholine receptor (nAChR) blocker with a significantly lower affinity at the neuronal α3β2 subtype. Remarkably, all analogues retained the low nanomolar activity of native CIA toward muscle-type nAChRs but showed greatly improved resistance to degradation in human serum and, surprisingly, displayed up to 52-fold higher potency for the α3β2 neuronal nAChR subtype (IC50 1.3 nM). Comparison of nuclear magnetic resonance-derived structures revealed some differences that might explain the gain of potency at α3β2 nAChRs. All peptides were highly paralytic when injected into adult zebrafish and bath-applied to zebrafish larvae, suggesting barrier-crossing capabilities and efficient uptake. Finally, these cyclic CIA analogues were shown to be unique pharmacological tools to investigate the contribution of the presynaptic α3β2 nAChR subtype to the train-of-four fade.

Marine organisms produce a diverse range of toxins and bioactive peptides to support predation, competition, and defense. The peptide repertoires of stony corals (order Scleractinia) remain relatively understudied despite the presence of tentacles used for predation and defense that are likely to contain a range of bioactive compounds. Here, we show that a tentacle extract from the mushroom coral, Heliofungia actiniformis, contains numerous peptides with a range of molecular weights analogous to venom profiles from species such as cone snails. Using NMR spectroscopy and mass spectrometry we characterized a 12-residue peptide (Hact-1) with a new sequence (GCHYTPFGLICF) and well-defined β-hairpin structure stabilized by a single disulfide bond. The sequence is encoded within the genome of the coral and expressed in the polyp body tissue. The structure present is common among toxins and venom peptides, but Hact-1 does not show activity against select examples of Gram-positive and Gram-negative bacteria or a range of ion channels, common properties of such peptides. Instead, it appears to have a limited effect on human peripheral blood mononuclear cells, but the ecological function of the peptide remains unknown. The discovery of this peptide from H. actiniformis is likely to be the first of many from this and related species.

The phylum Cnidaria contains a wide variety of unique organisms that possess interesting adaptations evolved over many years to help them survive in a competitive environment. One of these adaptations is the presence of venom, which has been of particular interest for studies aimed at identifying novel drug leads and for understanding the mechanisms involved in envenomation. The potency of the venom varies significantly amongst cnidarians, and although corals are often overshadowed by the jellyfish and sea anemone toxins, they also possess a range of interesting bioactive compounds. In this mini-review, we provide an overview of the toxins present in corals, highlighting the diverse structures and bioactivities.