Abstract by Iris Bea Ramiro

Somatostatin (SS) and its related peptides (SSRPs) belong to a family of hormones involved in various physiological roles. By studying deep-water fish-hunting cone snails (Group Protostomes, Phylum Mollusca, Family Conidae), we discovered a diverse family of SS-like peptides in cone snail venom, called consomatins.

In the first study, we characterized Consomatin Ro1, the first SS-like peptide isolated from cone snail venom. Consomatin Ro1 has been evolutionarily optimized to be more stable compared to the rapidly degraded SS. Consomatin Ro1 preferentially activated two of the five human somatostatin receptors (SSTs), SST₁ and SST₄, which are associated with analgesic activity. When tested in mice, we show that Consomatin Ro1 provided antihyperalgesia with similar effects to the known analgesic, morphine. In addition to the SST₁/SST₄-selective Consomatin Ro1, we also found other consomatins with distinct activation profiles at the human SSTs.

In the second study, a library of ~ 500 consomatins was identified and was used to investigate the SSRP family of signaling peptides in different phyla. Signaling peptides are widely present in both deuterostomes and protostomes, the two major groups of bilaterians. SSRP genes were previously found in deuterostomes, but the presence of SSRP genes in protostomes was uncertain. The discovery of consomatins in cone snails suggested the existence of a related SSRP-like signaling system in mollusks and other protostomes. We found that consomatins were recruited in the cone snail venom from an ancestral SSRP-like gene and that these genes are not only present in mollusks but also in many other protostome phyla. A comparison of SSRP-like genes and consomatins revealed that consomatins specifically evolved to target the receptors of prey.

In summary, this PhD project provided a library of compounds with distinct activity profiles that can be tapped for potential applications in pain, inflammation, and neuroendocrine disorders. Furthermore, with the SSRP-like signaling system as a case study, we show that venom peptides can be used to systematically uncover previously unknown signaling systems in various phyla.