Calcium Channel Blocking Polypeptides

Abstract

Venomous creatures produce a wealth of interesting peptide and protein toxins as components of their venoms. Many such peptide and protein toxins are potent and highly selective blockers or modulators of calcium channel function, and as such are valuable pharmacological tools and potentially valuable leads in human therapeutic development. Cone shells and spiders are rich sources of such toxins, although they are also found in scorpions and insects. In this chapter we compare the amino acid sequences of toxins active against calcium channels and describe their three dimensional structures and structure-function relationships. Certain structural motifs, in particular the inhibitor cystine knot, prove to be quite common amongst this class of toxins. Aspects of the pharmacology and physiology of these toxins in mammalian systems are discussed, with an emphasis on their application to the treatment of chronic pain. We then consider how these naturally occurring toxins might be mimicked in non-peptide (peptidomimetic) compounds that could be useful therapeutically for the treatment of pain and in other indications.