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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target
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Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target

机译：疟疾二氢叶酸还原酶作为抗药性降低靶标药物开发的范例

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摘要

Malarial dihydrofolate reductase (DHFR) is the target of antifolate antimalarial drugs such as pyrimethamine and cydoguanil, the clinical efficacy of which have been compromised by resistance arising through mutations at various sites on the enzyme. Here, we describe the use of cocrystal structures with inhibitors and substrates, along with efficacy and pharmacokinetic profiling for the design, characterization, and preclinical development of a selective, highly efficacious, and orally available antimalarial drug candidate that potently inhibits both wild-type and clinically relevant mutated forms of Plasmodium falciparum (Pf) DHFR. Important structural characteristics of P218 include pyrimidine side-chain flexibility and a carboxylate group that makes charge-mediated hydrogen bonds with conserved Arg122 (PfDHFR-TS amino acid numbering). An analogous interaction of P218 with human DHFR is disfavored because of three species-dependent amino acid substitutions in the vicinity of the conserved Arg. Thus, P218 binds to the active site of Pf DHFR in a substantially different fashion from the human enzyme, which is the basis for its high selectivity. Unlike pyrimethamine, P218 binds both wild-type and mutant Pf DHFR in a slow-on/slow-off tight-binding mode, which prolongs the target residence time. P218, when bound to PfDHFR-TS, resides almost entirely within the envelope mapped out by the dihydrofolate substrate, which may make it less susceptible to resistance mutations. The high in vivo efficacy in a SCID mouse model of P. falciparum malaria, good oral bioavailability, favorable enzyme selectivity, and good safety characteristics of P218 make it a potential candidate for further development.
机译：疟疾二氢叶酸还原酶（DHFR）是抗叶酸抗疟药的靶标，例如乙胺嘧啶和环鸟嘌呤，其临床功效已被酶各个位点突变引起的耐药性削弱。在这里，我们描述了共晶结构与抑制剂和底物的结合使用，以及功效和药代动力学概况分析，用于设计，表征和临床前开发的选择性，高效且可口服的抗疟药物候选物，该候选药物可有效抑制野生型和野生型。临床相关突变形式的恶性疟原虫（Pf）DHFR。 P218的重要结构特征包括嘧啶侧链柔韧性和与保守的Arg122形成电荷介导的氢键的羧基（PfDHFR-TS氨基酸编号）。 P218与人DHFR的类似相互作用不利，因为在保守的Arg附近存在三种依赖于物种的氨基酸取代。因此，P218以与人酶基本不同的方式结合于Pf DHFR的活性位点，这是其高选择性的基础。与乙胺嘧啶不同，P218以慢开/慢开紧密结合模式结合野生型和突变型Pf DHFR，从而延长了目标停留时间。当与PfDHFR-TS结合时，P218几乎完全位于由二氢叶酸底物绘制的包膜之内，这可能使其对耐药性突变的敏感性降低。在恶性疟原虫的SCID小鼠模型中的高体内功效，良好的口服生物利用度，有利的酶选择性和P218的良好安全性使其成为进一步开发的潜在候选者。

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  • 作者

    Yongyuth Yuthavong; Bongkoch Tarnchompoo; Tirayut Vilaivan; Penchit Chitnumsub; Sumalee Kamchonwongpaisan; Susan A. Charman; Danielle N. McLennan; Karen L. White; Livia Vivas; Emily Bongard; Chawanee Thongphanchang; Supannee Taweechai; Jarunee Vanichtanankul; Roonglawan Rattanajak; Uthai Arwon; Pascal Fantauzzi; Jirundon Yuvaniyama; William N. Charman; David Matthews;

  • 作者单位

    BIOTEC, National Science and Technology Development Agency, Thailand Science Park, Pathumthani 12120, Thailand;

    BIOTEC, National Science and Technology Development Agency, Thailand Science Park, Pathumthani 12120, Thailand;

    Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand;

    BIOTEC, National Science and Technology Development Agency, Thailand Science Park, Pathumthani 12120, Thailand;

    BIOTEC, National Science and Technology Development Agency, Thailand Science Park, Pathumthani 12120, Thailand;

    Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Australia;

    Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Australia;

    Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Australia;

    London School of Hygiene and Tropical Medicine, University of London, London WC1E 7HT, England;

    London School of Hygiene and Tropical Medicine, University of London, London WC1E 7HT, England;

    BIOTEC, National Science and Technology Development Agency, Thailand Science Park, Pathumthani 12120, Thailand;

    BIOTEC, National Science and Technology Development Agency, Thailand Science Park, Pathumthani 12120, Thailand;

    BIOTEC, National Science and Technology Development Agency, Thailand Science Park, Pathumthani 12120, Thailand;

    BIOTEC, National Science and Technology Development Agency, Thailand Science Park, Pathumthani 12120, Thailand;

    BIOTEC, National Science and Technology Development Agency, Thailand Science Park, Pathumthani 12120, Thailand;

    Medicines for Malaria Venture, 1215 Geneva, Switzerland;

    Department of Biochemistry and Center for Excellence in Protein Structure and Function, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;

    Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Australia;

    Medicines for Malaria Venture, 1215 Geneva, Switzerland;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    drug resistance; drug target; structure-informed drug discovery; slow-binding inhibitors; 2,4-diaminopyrimidines;

    机译：耐药性;药物目标结构相关的药物发现;慢结合抑制剂2,4-二氨基嘧啶;

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