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

• 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
• 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

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)：通过该试点，将利用核磁共振对布氏锥虫主要组织蛋白L的溶液骨架结构进行指认，并将解决布鲁氏支原体主要组织蛋白L的溶液结构。此外，除了合成已知的罗得西亚低微摩尔范围抑制剂的新衍生物外，我们还将从天然产品提取物中鉴定罗地松抑制剂的特征。分配罗地沙的主干结构将使基于溶液的抑制剂筛选成为可能，也有助于对已知抑制剂的优化，使它们具有更高的特异性和更高的效力，并有可能成为新型抗锥虫药物的先导。被忽视的热带病影响着世界上10多亿人口，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 根除这些疾病并为其提供治疗选择仍然至关重要。人类非洲锥虫病是由布氏锥虫引起的，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，目前的化疗方法在很大程度上是有毒的。仍然迫切需要继续研究开发更好、更安全的抗锥虫药。在过去的十年里，布鲁氏毛滴虫已经确定了几个药物靶点，这种寄生虫中最有希望和最有效的药物靶点之一是组织蛋白酶-L样蛋白酶罗得森。这一试点项目目标的实现将增加对抑制罗地沙很重要的结构特征的了解，并为抗锥虫药物的发现提供新的化学类型。