Post-translationally modified conopeptides: Biological activities and pharmacological applications

Conus venoms comprise a large variety of biologically active peptides (conopeptides or conotoxins) that are employed for prey capture and other biological functions. Throughout the course of evolution of the cone snails, they have developed an envenomation scheme that necessitates a potent mixture of peptides, most of which are highly post-translationally modified, that can cause rapid paralysis of their prey. The great diversity of these peptides defines the ecological interactions and evolutionary strategy of cone snails. Such scheme has led to some pharmacological applications for pain, epilepsy, and myocardial infarction, that could be further explored to ultimately find unique peptide-based therapies. This review focuses on ∼ 60 representative post-translationally modified conopeptides that were isolated from Conus venoms. Various conopeptides reveal post-translational modifications of specific amino acids, such as hydroxylation of proline and lysine, gamma-carboxylation of glutamate, formation of N-terminal pyroglutamate, isomerization of l- to d-amino acid, bromination of tryptophan, O-glycosylation of threonine or serine, sulfation of tyrosine, and cysteinylation of cysteine, other than the more common disulfide crosslinking and C-terminal amidation. Many of the post-translationally modified peptides paved the way for the characterization, by alternative analytical methods, of other pharmacologically important peptides that are classified under 27 conopeptide families denoting pharmacological classes.