Antifolates as Antimalarial Drugs

抗叶酸剂作为抗疟药

基本信息

批准号：
7166083
负责人：
Carol Hopkins Sibley
金额：
$ 35.82万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-01 至 2009-12-31
项目状态：
已结题

项目摘要

We have chosen to concentrate on a thorough understanding of the oldest family of antimalarials, 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 ofP. 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.

我们选择了对最古老的抗毒剂家族的坦白，即我们的抗肉在过去的几年中，工作表明，对这些抑制剂的抵抗力的彻底了解选定可以延长当前可用的抗脱脂药（如乙胺胺）的有用治疗寿命。重要的是，这些研究还表明，扔了被扔到theweration抗叶酸WR99210，这是Asan的巨大诺言负担得起的抗疟药将在长期内生效。抗性的抗性突变体。选择的是毒品开发人员经常寻求的“悬挂果”！我们在这笔赠款中提出，以确定区分区分作用的生化，遗传和生物学机制先前已经开发的丙烯胺和其他抗叶酸药物的WR99210。挥之不去我们将分析对DHFR抑制剂抗性的突变酶的生化参数。挥之不去我们将在体外分析DHFR突变等位基因在恶性疟原虫和息肉白斑中的适应性挥之不去我们将分析mRNA，蛋白质和小分子的池的变化，以确定变化这是用DHFR的吸入者，Surfa药物和两个协同组合中的药物。我们认为，这深刻理解了寄生虫中的防腐作用，将确保WR99210将是长期以来一直反对恶性疟原虫和Vivax的药物开发。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pyrimethamine-resistant dihydrofolate reductase enzymes of Plasmodium falciparum are not enzymatically compromised in vitro.

恶性疟原虫的乙胺嘧啶抗性二氢叶酸还原酶在体外不会受到酶促损害。

DOI：
10.1016/j.molbiopara.2007.03.009
发表时间：
2007
期刊：
Molecular and biochemical parasitology
影响因子：
1.5
作者：
Sandefur,ConnerI;Wooden,JasonM;Quaye,IsaacK;Sirawaraporn,Worachart;Sibley,CarolHopkins
通讯作者：
Sibley,CarolHopkins

A database of antimalarial drug resistance.