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治疗方法的主要障碍是无法找到具有足够特异性的安全有效的小分子。申请人团队汇集了一套独特的互补研究兴趣和技能，在分子水平上使用concontoxins来确定rho- concontoxins如何作用于α - 1肾上腺素受体（心血管和相关疾病的主要药物靶点）。rhoo -conotoxin是一种新型的α - 1肾上腺素受体肽抑制剂，似乎在一个未描述的变构部位起作用。本项目将使用rhoo -conotoxins和类似物来表征这类conopepides的结构和功能如何以及在哪里起作用。建立rhoo - concontoxins的构效关系，指导亚型特异性抑制剂的开发。α 1-肾上腺素受体和TIA之间的成对相互作用将用于将TIA连接到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疾病和相关疾病开发新的、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.