Solution Structure and Novel Inhibitors of T. brucei Cathepsin L

布氏锥虫组织蛋白酶 L 的溶液结构和新型抑制剂

基本信息

批准号：
8664726
负责人：
Ifedayo Victor Ogungbe
金额：
$ 13.23万
依托单位：
JACKSON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-15 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8664726
关键词：
Africa Africa South of the Sahara African Trypanosomiasis Antiparasitic Agents Asia Award Binding Biological Factors Cathepsin L Chemical Structure Chemicals Collection Coupled Data Development Disease Docking Drug Targeting Fractionation Future Goals Human Individual Knowledge Label Modeling Molecular Molecular Models Natural Product Drug Parasites Peptide Hydrolases Pharmaceutical Preparations Pilot Projects Plant Extracts Plants Population Protease Inhibitor Public Health Recombinants Research Resolution Solutions South America Specificity Structure Techniques Testing Tropical Disease Trypanosoma Trypanosoma brucei brucei Uncertainty United States Universities Vertebral column X-Ray Crystallography base chemotherapy design divinyl sulfone drug discovery improved in vitro activity inhibitor/antagonist molecular modeling neglect novel programs public health relevance rhodesain screening virtual

项目摘要

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.

描述（申请人提供）：通过本试点项目，将利用NMR对布氏锥虫主要组织蛋白酶L的溶液主链结构进行归属，并解析布氏锥虫主要组织蛋白酶L的溶液结构。此外，除了合成已知低微摩尔范围罗得西亚抑制剂的新型衍生物外，我们还将表征来自天然产物提取物的罗得西亚抑制剂。确定罗得塞因的主链结构将有助于基于溶液的抑制剂筛选，并有利于已知抑制剂的优化，使它们具有更高的特异性和改进的效力，并有可能作为新型抗锥虫药物的先导化合物。被忽视的热带疾病影响着超过 10 亿世界人口，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。于是，继续努力根除这些疾病并为其提供治疗选择仍然至关重要。由布氏锥虫引起的非洲人类锥虫病是撒哈拉以南非洲公共卫生的主要威胁。非洲人类锥虫病是一种被忽视的热带疾病，目前的化疗主要是有毒的。仍然迫切需要继续研究开发更好、更安全的抗锥虫药物。在过去的十年里，已经从布氏锥虫中鉴定出了几个药物靶点，这种寄生虫中最有前途和最有效的药物靶点之一是组织蛋白酶-L样蛋白酶罗得赛因。该试点项目目标的实现将增加对罗得赛抑制重要的结构特征的了解，并提供可用于抗锥虫药物发现的新化学型。