Antifolates as Antimalarial Drugs

抗叶酸剂作为抗疟药

• 批准号: 6669815
• 负责人: Carol Hopkins Sibley
• 金额: $ 11.4万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6669815
• 关键词: Plasmodium; Plasmodium falciparum; alleles; antimalarial agents; clinical research; combination chemotherapy; computer simulation; dihydrofolate reductase; drug design /synthesis /production; drug resistance; enzyme activity; enzyme inhibitors; folate antagonist; human subject; human tissue; malaria; microorganism disease chemotherapy; molecular dynamics; patient oriented research; pharmacogenetics; pharmacokinetics; pharmacology; protozoal genetics; pyrimethamine; sulfanilamides; transfection

DESCRIPTION (provided by the applicant): We have chosen to concentrate on a thorough understanding of the oldest family of anti-malarials, the antifolates. Our work in the last few years has shown that a thorough understanding of why and how resistance to these inhibitors is selected can extend the useful therapeutic life of currently available antifolate drugs like pyrimethamine. More important, these studies have also shown that a third generation antifolate, WR99210, holds great promise as an affordable antimalarial that will be effective over a long period. It is effective even against the most pyrimethamine resistant mutants of P. falciparum that have been identified, and mutants resistant to WR99210 have not been easily selected. It is the "low hanging fruit" that drug developers often seek! We propose in this grant to determine the biochemical, genetic and biological mechanisms of action that distinguish WR99210 from pyrimethamine and other antifolate drugs that have been previously developed. * We will analyze the biochemical parameters of mutant enzymes that are resistant to DHFR inhibitors. * We will analyze the fitness of mutant alleles of dhfr in P. falciparum and P. vivax in vitro * We will analyze the changes in pools of mRNA, proteins and small molecules to determine the changes that characterize treatment of P. falciparum with inhibitors of DHFR, with sulfa drugs and with both drugs in synergistic combination. We think that this in depth understanding of antifolate action in the parasites will ensure that WR99210 will be developed as a useful drug for the long haul against P. falciparum and P. vivax.

描述（由申请人提供）：我们选择专注于对最古老的抗疟疾家族的抗臭虫。在过去的几年中，我们的工作表明，对为什么选择对这些抑制剂的耐药性的透彻了解可以延长当前可用的抗叶酸药（如乙胺嘧啶）的有用治疗寿命。更重要的是，这些研究还表明，第三代抗叶酸WR99210具有很大的承诺，作为负担得起的抗疟药，这将在长期内有效。即使针对已鉴定出的恶性疟原虫的最抗乙胺胺耐药突变体也有效，并且不容易选择对WR99210的突变体。药物开发人员经常寻求的是“低悬挂果”！我们建议在这笔赠款中确定将WR99210与乙胺嘌呤和其他先前开发的抗叶酸药物区分开的生化，遗传和生物学机制。 *我们将分析对DHFR抑制剂抗性的突变酶的生化参数。 *我们将分析DHFR的突变等位基因在恶性疟原虫和体外拟南芥中的适应性 *我们将分析mRNA，蛋白质和小分子的池的变化，以确定表征恶性疟原虫用DHFR抑制剂，Sulfa药物以及两种药物在协同组合中处理的变化。 我们认为，对寄生虫中抗卵形作用的这一深度了解将确保WR99210将作为长期以来对抗恶性疟原虫和vivax的有用药物开发。