SELECTIVE INHIBITION OF PYRIMIDINE SYNTHESIS IN MALARIA

疟疾中嘧啶合成的选择性抑制

• 批准号: 2057162
• 负责人: PRADIPSINH K. RATHOD
• 金额: $ 6.32万
• 依托单位: CATHOLIC UNIVERSITY OF AMERICA
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-01 至 1997-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2057162
• 关键词: DNA damage; Plasmodium falciparum; antimalarial agents; chemical kinetics; deoxyribonucleotides; enzyme inhibitors; enzyme mechanism; fluorine; laboratory mouse; malaria; monoclonal antibody; orotate; orotate phosphoribosyltransferase; purine /pyrimidine metabolism; pyrimidine analog; pyrophosphates; ribose phosphate; scintillation counter; synthetic peptide; tetrahydrofolates; thymidylate synthase

The broad, long-term goal of the RCDA candidate's research is to understand the biochemical determinants that allow for selective chemotherapy against malarial parasites. Previously, the PI identified 5-identified 5-fluoroorotate as a potent antimalarial agent that is selective in culture and curative in animal models of malaria. Recently, he showed that treatment of infected erythrocytes with nanomolar amounts of 5-fluoroorotate resulted in selective and efficient activation of 5-fluoroorotate to fluorinated nucleotides and near complete inactivation of thymidylate synthase. During the RCDA period, the PI will identify the enzymatic mechanisms which account for species-selective activation of 5-fluoroorotate to fluorinated nucleotides in malarial parasites and the PI will determine why malarial thymidylate synthase is so vulnerable to 5-fluoroorotate treatment. Finally, the consequences of thymidylate synthase inactivation will be evaluated by monitoring steady-stat levels of 2'-deoxyribonucleotides, by studying DNA fragmentation, and by determining clonal viability of 5- fluoroorotate-treated malarial parasites.

RCDA候选人研究的广泛，长期目标是了解 允许选择性化疗的生化决定因素 疟原虫。 以前，PI识别出5个识别的5-氟核酸盐为有效 在动物中具有选择性和治愈性的抗性剂 疟疾模型。 最近，他表明被感染的治疗 纳摩尔量5-氟甲酸酯的红细胞导致 5-氟核的选择性有效激活氟化 核苷酸和胸苷酸合酶几乎完全失活。 期间 RCDA时期，PI将识别酶促机制 说明5-氟核的物种选择性激活对氟化 疟原虫和PI中的核苷酸将决定疟疾的原因 胸苷酸合酶非常容易受到5-氟核治疗的影响。 最后，胸苷酸合酶失活的后果将是 通过监测2'-脱氧核糖核苷酸的稳态水平，通过 研究DNA碎片，并通过确定5--的克隆活力 氟氧酸酯处理的疟疾寄生虫。