Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Curr Protein Pept Sci. 2013 Sep;14(6):532-42. doi: 10.2174/13892037113149990069.
Cyclotides and conotoxins are two classes of disulfide-rich peptides that occur in plants and animals respectively and are the major focus of study in our laboratory. In the last three years there has been significant progress in studies of these two classes of compounds and in this article we provide an overview of the findings from our laboratory in this period. Highlights include the discovery of cyclotides in the Fabaceae and Solanaceae plant families, members of which are widely used in human nutrition, and the discovery of new classes of cyclotide precursors. These discoveries confirm the widespread distribution of cyclotides in the plant kingdom and the diversity of precursor proteins involved in their biosynthesis. Other studies have delineated the mode of action of naturally occurring cyclotides and have demonstrated the versatility of synthetic cyclotides as stable protein engineering frameworks, with applications in drug design. Conotoxins continue to be a rich source of inspiration for drug design programs, and we summarize here a range of recent studies from our laboratory focusing on the development of novel synthetic strategies and the delineation of structure-activity relationships. A major highlight was the development of an orally active cyclized conotoxin derivative that is highly efficacious in a rat model of neuropathic pain. Overall the studies described herein provide much encouragement for continuing efforts to develop peptides as drugs.
环肽和芋螺毒素是分别存在于植物和动物中的两类富含二硫键的肽，也是我们实验室的主要研究焦点。在过去的三年中，这两类化合物的研究取得了显著进展，本文概述了我们实验室在此期间的研究成果。本文的重点包括在豆科和茄科植物家族中发现的环肽，其中一些广泛用于人类营养，以及发现新的环肽前体类别。这些发现证实了环肽在植物界中的广泛分布以及参与其生物合成的前体蛋白的多样性。其他研究阐明了天然环肽的作用模式，并证明了合成环肽作为稳定的蛋白质工程框架的多功能性，可应用于药物设计。芋螺毒素仍然是药物设计项目的丰富灵感来源，我们在此总结了我们实验室的一系列近期研究，重点是开发新型合成策略和阐明结构-活性关系。一个主要的亮点是开发出一种具有口服活性的环化芋螺毒素衍生物，在大鼠神经病理性疼痛模型中具有高度疗效。总体而言，本文所述的研究为继续努力将肽类开发成药物提供了很大的鼓舞。
