Novel peptides for the treatment of pain

五分之一的澳大利亚人患有慢性疼痛，神经性疼痛是慢性疼痛中最严重的一种。从锥体蜗牛毒液中提取的几种多肽作为治疗神经性疼痛的潜在药物引起了人们的关注。其中一种是concontoxin MVIIA，最近已在美国和欧洲获得批准，其他药物包括CVID和ACVI，正处于不同的临床研究阶段。这些小的富含二硫化物的肽具有肽一般具有对特定受体具有良好选择性的吸引人的特点，但也具有肽的生物半衰期短和生物利用度差的一般缺点。稳定这些concontoxins有可能大大增加其治疗潜力。在初步研究中，我们已经表明，通过使用连接子序列将圆形肽骨架引入螺毒素，我们可以增加其稳定性和抗酶降解能力。因此，我们建议有可能环化各种各样的螺毒素分子，从而改善它们的药物性质。在这个项目中，我们将使用我们的循环方法来开发新的潜在的治疗疼痛的两类concontoxin。其中一种先导分子在动物疼痛模型中显示出口服生物利用度，可能代表着肽药物递送领域的重大突破。

Chronic pain affects 1 in 5 Australians and neuropathic pain is among the most severe forms of chronic pain. Several peptides derived from cone snail venoms have attracted recent attention as potential therapeutic agents for the treatment of neuropathic pain. One of these, conotoxin MVIIA, has recently been approved in the US and Europe and others, including CVID and ACVI, are in various stages of clinical investigation. These small disulfide rich peptides share the attractive features of peptides in general of having exquisite selectivity for particular receptors, but also share the general disadvantages of peptides of short biological half-lives and poor bioavailablility. Stabilisation of these conotoxins has the potential to substantially increase their therapeutic potential. In preliminary studies we have shown that by introducing a circular petide backbone into a conotoxin using a linker sequence we can increase its stability and resistance to enzymatic degradation. We therefore propose that it will be possible to cyclise a wide range of conotoxin molecules and thereby improve their drug like properties. In this project we will use our cyclisation approach to develop new potential treatments for pain from two classes of conotoxins. One of the lead molecules shows oral bioavailability in an animal pain model and potentially represents a major breakthrough in the field of peptide drug delivery.