Bradykinin-potentiating and related peptides from reptile venoms

Abstract

Evolution has provided venomous snakes with a vast arsenal of molecules able to interfere in several physiological processes. The ultimate role of these toxins, which are proteins or peptides, is to subdue the prey, although digestive functions should also be considered. Among these toxins, some are vasoactive peptides, which induce a drastic drop in blood pressure. This effect is attributed mostly to bradykinin-potentiating peptides, although other venom peptides have been shown to interfere with blood pressure. Bradykinin-potentiating peptides are modular in nature, with highly conserved motifs, and present high proline content, a pyroglutamate at the N-terminal and an IPP motif at the C-terminal. These peptides are potent and highly selective inhibitors of angiotensin-converting enzyme, a crucial molecule for blood pressure regulation, and display K i s as low as 8 nM. Besides the enzyme inhibition, some of these peptides might cross the cell membrane, interfering in the production of nitric oxide, another modulator of blood vessel tonus. Evolution frequently results in physiological redundancies. Such a fact is reflected by the occurrence of another class of blood pressure–modulating toxins. C-type natriuretic peptides can be considered as such. Apparently, these toxins increase guanylate cyclase levels, inducing vasorelaxation. These peptides are being considered as drug leads for congestive heart failure. While C-type natriuretic peptides are still under investigation as potential drugs, bradykinin-potentiating peptide–derived drugs are the boldest example of the use of a deleterious “toxin” as a building block for a cheap drug that benefits a huge number of human beings.