Novel Anti-Malarials by Combinatorial Pharmacogenomics

组合药物基因组学的新型抗疟药

• 批准号: 6665332
• 负责人: JOSEPH L. DERISI
• 金额: $ 83.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6665332
• 关键词: Plasmodium falciparum; antimalarial agents; chemical information system; clinical research; combinatorial chemistry; cooperative study; drug design /synthesis /production; drug screening /evaluation; erythrocytes; flow cytometry; functional /structural genomics; high throughput technology; human subject; laboratory rat; liver cells; malaria; microarray technology; quinoline; tissue /cell culture

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.

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.合作完成，和斯坦福大学研究所（SRI），Inc. 喹啉类药物在抗疟疾方面有着悠久而丰富的历史，但迄今为止，受试化合物的多样性受到合成技术范围狭窄的限制。 关于这些药物在分子水平上对寄生虫的影响知之甚少。 因此，在全基因组水平上的额外信息可以大大加速对这些化合物的理解和对它们结构的优化，以达到颠覆寄生虫的目的。 Guy实验室将实施一项组合合成计划，旨在生成编码约80%新型喹啉的文库，并在高通量体外测定系统中测试它们对恶性疟原虫的活性。 与此同时，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合成工作中出现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。 顶尖的候选人也将被转移到SRI公司，进行严格的毒理学测试 将使用GenoSpectra，Inc.开发的全人类基因组芯片，使用候选化合物处理的肝细胞培养物的RNA材料收集表达反应。 从已知的抗疟疾药物，新型喹啉和毒理学的编译关系，然后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。