Selectivity and mode of action of rho-conopeptide TIA: A novel inhibitor of alpha1-adrenoceptors.

开发更安全、更有效的心血管疾病和良性前列腺增生症治疗方法的一个主要障碍是无法找到足够特异性的小分子来安全和有效。申请团队汇集了一系列独特的互补研究兴趣和技能，利用芋螺毒素在分子水平上定义螺芋螺毒素如何在α1肾上腺素受体上发挥作用，这是心血管和相关疾病的主要药物靶标。芋螺毒素是一种新型的α1-肾上腺素能受体的多肽抑制剂，它似乎作用于一个未知的变构部位。该项目将使用螺螺毒素及其类似物从结构和功能上描述这类椰子如何起作用以及在哪里起作用。将建立螺芋螺毒素的构效关系，指导亚型特异性抑制剂的开发。α1-肾上腺素受体和TIA之间的成对相互作用蛋白将被用于将TIA对接到α1-肾上腺素受体的同源模型上。该项目的长期目标是开发新的、更安全的心血管及相关疾病治疗方法。

A major obstacle to the development of safer and more effective treatments for cardivascular diseases and benign prostatic hyperplasia is the inability to find small molecules with sufficient specificity to be safe and effective. The applicant team brings together a unique set of complementary research interests and skills in using conotoxins to define, at the molecular level, how rho-conotoxins act at the alpha1-adrenoceptor, a major drug target for cardiovascualr and related diseases. Rho-conotoxins are novel peptide inhibitors of the alpha1-adrenoceptor that appear to act at an undescribed allosteric site. This Project will use rho-conotoxins and analogues to characterise structurally and functionally how and where this class of conopepides act. The structure activity relationship for rho-conotoxins will be established to guide the development of subtype specific inhibitors. Pairwise interactins between the alpha1-adrenoceptorand TIA will be used to dock TIA onto a homolgy model of the alpha1-adrenoceptor. The long-term goal of the project is to develop new and safer treatments for cardiovascular and related disorders.