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

开发心血管疾病和良性前列腺增生的更安全和更有效的治疗方法的主要障碍是无法找到具有足够特异性的小分子，以确保安全和有效。申请人团队汇集了一套独特的互补研究兴趣和技能，使用芋螺毒素在分子水平上定义rho-芋螺毒素如何作用于α 1-肾上腺素受体，这是心血管和相关疾病的主要药物靶点。Rho-芋螺毒素是α 1-肾上腺素受体的新型肽抑制剂，其似乎作用于未描述的变构位点。本计画将利用rho-芋螺毒素及其类似物来研究这类芋螺肽的结构与功能。建立芋螺毒素的构效关系，为开发亚型特异性抑制剂提供理论指导。α 1-肾上腺素受体和TIA之间的成对相互作用将用于将TIA对接到α 1-肾上腺素受体的同源模型上。该项目的长期目标是为心血管和相关疾病开发新的和更安全的治疗方法。

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.