The Terebridae and teretoxins: Combining phylogeny and anatomy for concerted discovery of bioactive compounds

摘要

The Conoidea superfamily, comprised of cone snails, terebrids, and turrids, is an exceptionally promising group forthe discovery of natural peptide toxins. The potential of conoidean toxins has been realized with the distribution ofthe first Conus (cone snail) drug, Prialt (ziconotide), an analgesic used to alleviate chronic pain in HIV and cancerpatients. Cone snail toxins (conotoxins) are highly variable, a consequence of a high mutation rate associated toduplication events and positive selection. As Conus and terebrids diverged in the early Paleocene, the toxins fromterebrids (teretoxins) may demonstrate highly divergent and unique functionalities. Recent analyses of the Terebri-dae, a largely distributed family with more than 300 described species, indicate they have evolutionary and phar-macological potential. Based on a three gene (COI, 12S and 16S) molecular phylogeny, including ~50 species fromthe West-Pacific, five main terebrid lineages were discriminated: two of these lineages independently lost theirvenom apparatus, and one venomous lineage was previously unknown. Knowing the phylogenetic relationshipswithin the Terebridae aids in effectively targeting divergent lineages with novel peptide toxins. Preliminary resultsindicate that teretoxins are similar in structure and composition to conotoxins, suggesting teretoxins are an attrac-tive line of research to discover and develop new therapeutics that target ion channels and receptors. Using cono-toxins as a guideline, and innovative natural products discovery strategies, such as the Concerted DiscoveryStrategy, the potential of the Terebridae and their toxins are explored as a pioneering pharmacological resource.