Novel peptides for the treatment of pain

用于治疗疼痛的新型肽

• 批准号: nhmrc : 456074
• 负责人: Dr Richard Clark
• 金额: $ 20.26万
• 依托单位: The University of Queensland
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/novel-peptides-treatment-pain/76267
• 关键词: Novel; peptides; treatment; pain

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.

慢性疼痛影响着五分之一的澳大利亚人，神经性疼痛是慢性疼痛中最严重的形式之一。近年来，从锥形蜗牛毒液中提取的几种多肽作为治疗神经病理性疼痛的潜在药物引起了人们的关注。其中一种是芋螺毒素MVIIA，最近已在美国和欧洲获得批准，其他包括CVID和ACVI在内的药物正处于不同的临床研究阶段。这些富含二硫键的小分子多肽具有与一般多肽相同的特点，即对特定受体具有极好的选择性，但也有生物半衰期短、生物利用度低的缺点。这些芋螺毒素的稳定有可能大幅提高它们的治疗潜力。在初步的研究中，我们已经表明，通过使用连接子序列将环肽骨架引入到螺毒素中，我们可以增加其稳定性和对酶降解的抵抗力。因此，我们提出，有可能使范围广泛的芋螺毒素分子环化，从而改善它们的类药物性质。在这个项目中，我们将使用我们的循环方法来开发两种芋螺毒素产生的疼痛的新的潜在治疗方法。其中一种先导分子在动物疼痛模型中显示了口服生物利用度，并可能代表着多肽药物输送领域的重大突破。