Clark Richard J, Craik David J
School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia.
Methods Enzymol. 2012;503:57-74. doi: 10.1016/B978-0-12-396962-0.00003-3.
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.
近年来，基于肽的毒素因其在药物设计与开发中令人兴奋的潜在应用而备受关注。这种兴趣的产生是因为毒素具有高效性且能选择性地作用于一系列生理上重要的受体。然而，肽存在许多缺点，包括体内稳定性差和生物利用度低。在植物、动物和细菌中发现了一些天然存在的环肽，它们具有出色的稳定性，并有可能改善这些缺点。从对这些环肽的结构、稳定性和生物活性的研究中获得的经验教训，可应用于对非天然环化但适合环化的毒素进行重新设计。在本章中，我们描述了用于重新设计肽毒素以提高其作为治疗、诊断或成像剂适用性的固相化学合成方法。重点是来自芋螺和蝎子毒液的富含二硫键的小肽，但该技术可能广泛适用于许多其他基于肽的毒素。
