Solution Structure and Novel Inhibitors of T. brucei Cathepsin L

描述（由申请人提供）：通过该试点项目，T。利用核磁共振技术对布氏主要组织蛋白酶L进行了归属，并对T.布氏主要组织蛋白酶L将被解决。此外，我们将从天然产物提取物的特性，除了合成已知的低微摩尔范围的罗得西亚抑制剂的新衍生物的罗得西亚蛋白抑制剂。研究罗地蛋白的骨架结构将使基于溶液的抑制剂筛选成为可能，也有助于优化已知的抑制剂，使其具有更高的特异性和改善的效力，并可能作为新型抗锥虫药物的先导。被忽视的热带疾病影响着世界上10亿多人口，主要集中在亚洲、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，继续努力 根除这些疾病并提供治疗选择仍然至关重要。由布氏锥虫引起的人类非洲锥虫病是撒哈拉以南非洲公共卫生的主要威胁。人类非洲锥虫病是一种被忽视的热带疾病，目前的化学疗法在很大程度上是有毒的。仍然迫切需要继续研究，以开发更好和更安全的抗锥虫药物。几种药物靶标已经从T.在过去的十年中，布氏杆菌是最有前途的和有效的药物靶标之一，在这种寄生虫中，组织蛋白酶-L样蛋白酶玫瑰色蛋白酶。该试验项目目标的实现将增加对罗地蛋白酶抑制重要的结构特征的知识，并提供可用于抗锥虫药物发现的新化学型。

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.