Novel Anti-Malarials by Combinatorial Pharmacogenomics

描述（由申请人提供）：拟议工作的目标是开发新型喹啉类抗疟疾化合物。这项工作将由两个学术实验室Kip Guy和Joseph DeRisi，以及两个工业合作伙伴GenoSpectra， Inc.和斯坦福研究所（SRI）， Inc.合作完成。喹啉类药物在抗疟疾方面有着悠久而丰富的使用历史，但迄今为止所测试化合物的多样性受到有限的合成技术的限制。人们对这些药物在分子水平上对寄生虫的作用知之甚少。因此，全基因组水平上的额外信息可以大大加快对这些化合物的理解，并优化其结构，以达到颠覆寄生虫的目的。Guy实验室将实施一个组合合成程序，旨在生成一个编码约80%新喹啉的文库，并在高通量体外检测系统中测试它们对恶性疟原虫的活性。同时，盖伊实验室将为已知和测试的喹啉结构制作并公开提供结构活性数据库。DeRisi实验室将开始使用近全基因组阵列和新型生物反应器生长系统对所有已知和可用的抗疟疾疗法进行表达谱分析。已知抗疟疾药物的表达数据将与Guy Lab合成的顶级候选化合物的表达数据结合使用，以创建结构-活性表达关系。最优秀的候选人也将被转移到SRI公司进行严格的毒理学测试。从经过候选化合物处理的培养肝细胞中提取的RNA材料将用于使用GenoSpectra公司开发的全人类基因组芯片收集表达反应。从已知的抗疟疾药物、新型喹啉类药物和毒理学中收集的关系将用于指导和优化额外的合成工作，以实现生产有效治疗药物的最终目标。

DESCRIPTION (provided by applicant): The goal of the proposed work is the development of novel quinoline-based anti-malarial compounds. The work will be accomplished by the cooperation of of two academic labs, Kip Guy and Joseph DeRisi, and two industrial partners, GenoSpectra, Inc., and Stanford Research Institute (SRI), Inc. Quinolines have a long and rich history of anti-malarial use, yet the diversity of tested compounds to date has been limited by a narrow range of synthetic techniques. Little is known about the effects these drugs have on parasites at the molecular level. Additional information at the whole genome level could thus greatly accelerate both the understanding of these compounds and the optimization of their structure for the purpose of subverting the parasite. The Guy Lab will implement a combinatorial synthesis program aimed at generating a library encoding approximately 80% novel quinolines and test them for activity against Plasmodium falciparum in a high throughput in vitro assay system. In parallel, the Guy Lab will produce and make publicly available a structure activity database for known and tested quinoline structures. The DeRisi lab will commence expression profiling of all the known and available anti-malarial therapeutics using a near-whole genome array and a novel bioreactor growth system. Expression data for known anti-malarial drugs will be used in combination with expression data gathered for top candidate compounds emerging from the Guy Lab synthesis effort to create a structure-activity expression relationship. Top candidates will also be transferred to SRI, Inc., for rigorous toxicology testing. RNA material from cultured hepatocytes treated with candidate compounds will be used to gather expression responses using whole human genome chips developed by GenoSpectra, Inc. The compiled relationships from known anti-malarials, novel quinolines, and toxicology will then be used to guide and optimize additional synthesis efforts toward the ultimate goal of producing effective therapeutics.