ANTIMALARIAL ACTIVITY OF OROTIC ACID ANALOGS

乳清酸类似物的抗疟活性

• 批准号: 3454868
• 负责人: PRADIPSINH K. RATHOD
• 金额: $ 8.91万
• 依托单位: CATHOLIC UNIVERSITY OF AMERICA
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-01 至 1994-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3454868
• 关键词: DNA; Plasmodium falciparum; RNA; antimalarial agents; antimetabolites; autoradiography; drug design /synthesis /production; drug metabolism; drug screening /evaluation; enzyme inhibitors; enzyme mechanism; erythrocytes; gel electrophoresis; high performance liquid chromatography; intracellular parasitism; malaria; nucleotide analog; parasitic disease chemotherapy; pharmacokinetics; radionuclides; scintillation spectrometry; thymidylate synthase; ultraviolet spectrometry

In recent decades Plasmodium falciparum has re-emerged as the major health threat in most tropical regions of the world. We have recently demonstrated, in vitro, that 5-fluoroorotate is exceedingly toxic to P. falciparum (IC30=6x10-9M). In contrast, 5-fluoroorotate is much less toxic to human fibrosarcoma cells (IC30=5x10-5M). Furthermore, the combination of uridine and 5-fluoroorotate says mammalian cells from toxicity without compromising the antimalarial activity of 5-fluoroorotate. Finally, 5- fluoroorotate is very effective against multiple drug-resistant parasites. The primary goal of the proposed research is to determine the molecular basis for the selective antimalarial activity of 5-fluoroorotate. We will characterize the transport of 5-fluoroorotate into erythrocytes infected with asynchronous as well as synchronous populations of P. falciparum. We will also follow the metabolism of radioactive drug into nucleotides and into macromolecules such as RNA, and the enzyme thymidylate synthetase. Experiments will be performed to determine whether inactivation of malarial thymidylate synthetase plays a role in whether inactivation of malarial thymidylate synthetase plays a role in whether inactivation of malarial thymidylate synthetase plays a role in 5-fluoroorotate toxicity. Kinetic interactions between parasite 5-fluoro 2' -deoxyuridylate will be analyzed. A new antimetabolite, trans 5-fluorodihydrocrotate will be synthesized and tested as a selective antimalarial drug. If successful in vitro, it will tell us that derivatives of dihydroorotate may also be highly effective antimalarial drugs.

近几十年来，恶性疟原虫重新成为主要的健康威胁。 在世界上大多数热带地区的威胁。我们最近 证明，在体外，5-氟乳清酸是非常有毒的P。 恶性疟原虫（IC_（30）= 6 × 10 ~（-9）M）。相比之下，5-氟乳清酸盐的毒性要小得多 对人纤维肉瘤细胞（IC 30 = 5 × 10 - 5 M）。此外， 尿苷和5-氟乳清酸说，哺乳动物细胞从毒性没有 损害了5-氟乳清酸盐的抗疟疾活性。最后，5- 氟乳清酸盐对多种抗药性寄生虫非常有效。 这项研究的主要目标是确定 5-氟乳清酸选择性抗疟活性的基础。我们将 表征5-氟乳清酸转运到感染的红细胞中 恶性疟原虫的异步和同步种群。我们 也会跟随放射性药物代谢成核苷酸， 转化为大分子如RNA和胸苷酸合成酶。 将进行实验以确定是否灭活疟疾 胸苷酸合成酶在疟疾病毒失活中起作用 胸苷酸合成酶在疟疾病毒失活中起作用 胸苷酸合成酶在5-氟乳清酸毒性中起作用。 动力学 将分析寄生虫5-氟2 ′-脱氧尿苷酸之间的相互作用。 本论文拟合成一种新的抗代谢药反式5-氟二氢巴豆酸， 作为一种选择性抗疟疾药物进行测试。如果在体外成功， 告诉我们二氢乳清酸衍生物也可能是非常有效的 抗疟疾药物。