CHAPTER 11: Engineering Venom Peptides to Improve Their Stability and Bioavailability

Peptides are regarded as an exciting new class of potential therapeutics but have in the past been perceived to have limitations in terms of stability and bioavailability. Disulfide-rich peptides from venoms have the potential to overcome some of these traditional shortcomings of peptides, particularly as disulfide bonding can dramatically stabilize peptides. Such venom peptides can be further stabilized by additional chemical engineering modifications, and our laboratory has focused on the cyclization of peptides as a means of stabilizing them and potentially making them orally active. Here we describe approaches for the head-to-tail backbone cyclization of a range of conotoxins from cone snail venoms. The cyclization technology has now been exemplified for several classes of conotoxins and, in general, cyclization causes a significant increase in the stability of peptides in biofluids. In the case of conotoxin Vc1.1, cyclization had the additional, and highly significant, benefit of engendering the peptide with oral activity. In that case the naturally occurring linear peptide has activity in a rat model of neuropathic pain when injected but is not active orally. The cyclized molecule is more potent and is orally active, illustrating the dramatic benefit of cyclization. We believe this cyclization approach can be generalized to a wide range of proteins, thereby increasing the value of peptides in drug design.