Solution Structure and Novel Inhibitors of T. brucei Cathepsin L

描述（申请人提供）：通过本试点项目，利用核磁共振技术对布鲁氏主要组织蛋白酶L的溶液骨架结构进行赋值，求解布鲁氏主要组织蛋白酶L的溶液结构。此外，我们将从天然产物提取物中表征罗得西亚蛋白酶抑制剂，以及合成已知的低微摩尔范围罗得西亚抑制剂的新衍生物。确定罗得西亚蛋白酶的主链结构将使基于溶液的抑制剂筛选成为可能，也有助于优化已知抑制剂，使它们具有更高的特异性和更好的效力，并有可能作为新型抗锥虫药物的先导。被忽视的热带病影响着世界上超过10亿的人口，主要分布在亚洲、非洲和南美洲，这些疾病对包括美国在内的全球公共卫生构成重大威胁。因此，持续的努力

DESCRIPTION (provided by applicant): Through this pilot project, the solution backbone structure of T. brucei's major cathepsin L will be assigned using NMR, and the solution structure of T. brucei's major cathepsin L will be solved. Also, we will characterize rhodesain inhibitory agents from natural product extracts in addition to synthesizing novel derivatives of known low micromolar range inhibitors of rhodesian. Assigning the backbone structure of rhodesain will enable solution-based screening of inhibitors and also facilitate the optimization of known inhibitors so that they can have higher specificity and improved potency, and potentially serve as leads for novel antitrypanosomal drugs. Neglected tropical diseases impact over 1 billion of the world's population predominantly in Asia, Africa and South America and these diseases pose significant threat to global public health including the United States. Thus, continued effort to eradicate and provide treatment options for these diseases remain crucial. Human African Trypanosomiasis, caused by Trypanosoma brucei, is a major threat to public health in sub-Saharan Africa. Human African Trypanosomiasis is a neglected tropical disease and is a disease that the current chemotherapies are largely toxic. There remains a critical need for continued research towards the development of better and safer antitrypanosomal drugs. Several drug targets have been characterized from T. brucei in the last decade and one of the most promising and validated drug targets in this parasite is the cathepsin-L like protease rhodesain. The realization of the aims for this pilot project will add to the knowledge of structurl features important for rhodesain inhibition as well as provide new chemotypes that can be explored for antitrypanosomal drug discovery.