Antifolates as Antimalarial Drugs

抗叶酸剂作为抗疟药

• 批准号: 6795562
• 负责人: Carol Hopkins Sibley
• 金额: $ 34.59万
• 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/6795562
• 关键词: Antifolates; Antimalarial; Drugs

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）：我们选择集中精力全面了解最古老的抗疟疾药物——抗叶酸药物。我们过去几年的工作表明，彻底了解为什么以及如何选择对这些抑制剂的耐药性可以延长目前可用的抗叶酸药物（如乙胺嘧啶）的有效治疗寿命。更重要的是，这些研究还表明，第三代抗叶酸剂 WR99210 作为一种经济实惠、长期有效的抗疟药具有广阔的前景。它甚至对已鉴定的最具有乙胺嘧啶抗性的恶性疟原虫突变体也有效，并且对 WR99210 具有抗性的突变体尚未轻易选择。这是药物开发商经常寻求的“容易实现的成果”！我们建议在这笔拨款中确定 WR99210 与乙胺嘧啶和先前开发的其他抗叶酸药物的区别的生化、遗传和生物作用机制。 * 我们将分析对 DHFR 抑制剂具有抗性的突变酶的生化参数。 * 我们将分析 dhfr 突变等位基因在恶性疟原虫和间日疟原虫中的体外适应性 * 我们将分析 mRNA、蛋白质和小分子库的变化，以确定 DHFR 抑制剂、磺胺类药物以及两种药物协同组合治疗恶性疟原虫的特征变化。 我们认为，对寄生虫抗叶酸作用的深入了解将确保 WR99210 将被开发为长期对抗恶性疟原虫和间日疟原虫的有用药物。