Discovery of Lead Compounds Against Trypanosomiasis and Leishmaniasis Through Ind

描述(申请人提供)：以前的原则证明研究将为发现和优化锥虫寄生虫(布氏锥虫、克氏锥虫和利什曼原虫)丙酮酸激酶(PYK)的选择性抑制剂奠定基础。这些病原体在热带和亚热带国家造成严重的、往往是致命的人类疾病，如昏睡病、恰加斯病和黑热病，主要是在非洲、中美洲和南美洲以及亚洲，那里有数百万人生活在疾病流行的地区。可悲的是，目前治疗这些疾病的药物并不令人满意，因为它们有毒，对某些形式的疾病无效，而且耐药性正变得越来越普遍。糖酵解在布氏毛滴虫中是必不可少的，因此是一个有希望的药物靶点。因此，PYK等糖酵解酶的抑制剂可以作为新药开发的先导化合物。这项研究的具体目标是：(1)利用锥虫PYK的独特特性(其详细的结构信息已经获得，并已被RNAi验证为药物靶标)，通过对包含30万个小分子的分子文库小分子库(MLSMR)的定量高通量筛选，从墨西哥锥虫(LmPYK)和布鲁氏锥虫(TbPYK)中发现PYK的选择性抑制剂；(2)在一组二次检测中确认这些化合物的效力，并测试对人PYK的选择性，并进一步提高通过基于结构的方法、类似物合成和药物化学原理获得的最有希望的分子的效力；。(3)测试具有最高效力的化合物，以抑制代表寄生虫致病阶段的培养细胞的生长。

DESCRIPTION (provided by applicant): Previous proof-of-principle research will provide the foundation for the discovery and optimization of selective inhibitors of pyruvate kinase (PYK) of trypanosomatid parasites (Trypanosoma brucei, T. cruzi and Leishmania species). These pathogens cause serious, often fatal diseases of humans such as sleeping sickness, Chagas' disease and kala-azar in tropical and subtropical countries primarily in Africa, Central and South America, and Asia where many millions live in areas where the diseases are endemic. Tragically, current drugs for their treatment are unsatisfactory because they are toxic and ineffective against some forms of the diseases, and resistance is becoming increasingly common. Glycolysis is essential in T. brucei and therefore a promising drug target. Inhibitors of glycolytic enzymes such as PYK may thus serve as lead compounds for the development of new drugs. The proposed research has as specific aims: (1) to exploit unique features of trypanosomatid PYK (for which detailed structural information is already available and which has been validated as drug target by RNAi) for the discovery of selective inhibitors of PYKs from L. mexicana (LmPYK) and from T. brucei (TbPYK) through quantitative high-throughput screening of the Molecular Library Small Molecule Repository (MLSMR) containing 300,000 small molecules; (2) To confirm the potency of these compounds in a panel of secondary assays and to test the selectivity against human PYK, and to further improve the potency of the most promising molecules thus obtained by structure-based methods, analogue synthesis and medicinal chemical principles; (3) To test compounds displaying the highest potency for their ability to inhibit growth of cultured cells representing pathogenic stages of the parasites.