Engineering cyclic peptide toxins.
Peptide-based toxins have attracted much attention in recent years for their exciting potential applications in drug design and development. This interest has arisen because toxins are highly potent and selectively target a range of physiologically important receptors. However, peptides suffer from a number of disadvantages, including poor in vivo stability and poor bioavailability. A number of naturally occurring cyclic peptides have been discovered in plants, animals, and bacteria that have exceptional stability and potentially ameliorate these disadvantages. The lessons learned from studies of the structures, stabilities, and biological activities of these cyclic peptides can be applied to the reengineering of toxins that are not naturally cyclic but are amenable to cyclization. In this chapter, we describe solid-phase chemical synthetic methods for the reengineering of peptide toxins to improve their suitability as therapeutic, diagnostic, or imaging agents. The focus is on small disulfide-rich peptides from the venoms of cone snails and scorpions, but the technology is potentially widely applicable to a number of other peptide-based toxins.
School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia.
Richard J
RJ
Clark
David J
DJ
Craik
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D020916:Conotoxins / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D052078:Conus Snail / Q000737:chemistry; D003500:Cyclization; D004220:Disulfides / Q000737:chemistry; D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D015202:Protein Engineering / Q000379:methods*; D055550:Protein Stability; D059748:Proteolysis; D012604:Scorpion Venoms / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D012605:Scorpions / Q000737:chemistry; D060327:Solid-Phase Synthesis Techniques / Q000379:methods*; D013329:Structure-Activity Relationship
D000596:Amino Acids; D020916:Conotoxins; D004220:Disulfides; D010456:Peptides, Cyclic; D012604:Scorpion Venoms; C091539:Chlorotoxin