Antifolates as Antimalarial Drugs

抗叶酸剂作为抗疟药

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7166083
• 关键词: African; Aftercare; Alleles; Antimalarials; Back; Binding; Biochemical; Biochemical Genetics; Biological; Biological Assay; Chloroquine; Condition; Country; DHFR gene; Data; Depth; Dihydrofolate Reductase; Dihydrofolate Reductase Inhibitor; Drug resistance; Engineering; Ensure; Enzymes; Escherichia coli; Family; Folic Acid Antagonists; Fruit; Generations; Genes; Genetic Translation; Grant; Growth; Histidine; In Vitro; Lead; Life; Messenger RNA; Methionine; Modeling; NADP; Numbers; Parasites; Pharmaceutical Preparations; Property; Proteins; Pyrimethamine; Pyrimethamine-Sulfadoxine; Rate; Relative (related person); Resistance; Serine; System; Tetrahydrofolates; Therapeutic; Thinking; Thymidine; Transfection; Work; Yeasts; chlorcycloguanil; cofactor; dihydrofolate; dihydropteroate; fitness; in vivo; inhibitor/antagonist; interest; mutant; novel; research study; response; small molecule; sulfa drug

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.

我们选择专注于彻底了解最古老的抗疟药家族——我们的抗叶酸药物。 过去几年的工作表明，深入了解对这些抑制剂产生耐药性的原因和方式 选择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。 重要的是，这些研究还表明，第三代抗叶酸剂 WR99210 作为一种药物具有广阔的前景。 价格实惠、长期有效的抗疟药，甚至对大多数乙胺嘧啶也有效。 恶性疟原虫的抗性突变体已被鉴定，而对 WR99210 的抗性突变体尚未轻易发现。 这是药物开发人员经常寻求的“容易实现的目标”！ 我们建议在这笔赠款中确定区分的生化、遗传和生物作用机制 WR99210来自乙胺嘧啶和先前开发的其他抗叶酸药物。 ¿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、蛋白质和小分子池的变化以确定变化 其特点是用 DHFR 抑制剂、磺胺类药物和两者一起治疗恶性疟原虫 在协同组合药物中。 我们认为，对寄生虫抗叶酸作用的深入了解将确保 WR99210 被开发为长期对抗恶性疟原虫和间日疟原虫的有用药物。

项目成果

Assessment of the origins and spread of putative resistance-conferring mutations in Plasmodium vivax dihydropteroate synthase.

评估间日疟原虫二氢蝶酸合酶中假定的抗性赋予突变的起源和传播。

• 发表时间: 2009-08
• 作者: Hawkins, Vivian N;Suzuki, Stephanie M;Rungsihirunrat, Kanchana;Hapuarachchi, Hapuarachchige C;Maestre, Amanda;Na;Sibley, Carol Hopkins
• 通讯作者: Sibley, Carol Hopkins

Characteristics of Plasmodium falciparum dhfr haplotypes that confer pyrimethamine resistance, Kilifi, Kenya, 1987--2006.

赋予乙胺嘧啶抗性的恶性疟原虫 dhfr 单倍型的特征，肯尼亚基利菲，1987--2006 年。

• 发表时间: 2008-06-15
• 作者: Certain, Laura K;Briceño, Marnie;Kiara, Steven M;Nzila, Alexis M;Watkins, William M;Sibley, Carol Hopkins
• 通讯作者: Sibley, Carol Hopkins

Point mutations in the dihydrofolate reductase and dihydropteroate synthase genes of Plasmodium falciparum and resistance to sulfadoxine-pyrimethamine in Sri Lanka.

斯里兰卡恶性疟原虫二氢叶酸还原酶和二氢叶酸合酶基因的点突变以及对磺胺多辛-乙胺嘧啶的抗性。

• 发表时间: 2006-02
• 作者: Hapuarachchi, Hapuarachchige C;Dayanath, Meegoda Y D;Bandara, Kandeyaye Bandaralage A T;Abeysundara, Sudusinghe;Abeyewickreme, Wimaladharma;de Silva, Nilanthi R;Hunt, Sonia Y;Sibley, Carol Hopkins
• 通讯作者: Sibley, Carol Hopkins

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。

• 发表时间: 2007-07
• 影响因子: 1.5
• 作者: Sandefur, Conner I;Wooden, Jason M;Quaye, Isaac K;Sirawaraporn, Worachart;Sibley, Carol Hopkins
• 通讯作者: Sibley, Carol Hopkins

Novel alleles of Plasmodium falciparum dhfr that confer resistance to chlorcycloguanil.

赋予对氯环胍抗性的恶性疟原虫 dhfr 的新等位基因。

• 发表时间: 2005-01
• 作者: Hunt, Sonia Y;Rezvani, Brian B;Sibley, Carol Hopkins
• 通讯作者: Sibley, Carol Hopkins