NOVEL ANTITUBERCULAR AGENTS VIA COMBINATORIAL CHEMISTRY

通过组合化学的新型抗结核药物

• 批准号: 2717407
• 负责人: KIRK MCMILLAN
• 金额: $ 10万
• 依托单位: PHARMACOPEIA DRUG DISCOVERY, INC.
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1998-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2717407
• 关键词: Mycobacterium tuberculosis; antitubercular agents; chemical synthesis; communicable disease control; drug design /synthesis /production; drug screening /evaluation; hydroxy fatty acid; tuberculosis

Tuberculosis is the leading cause of global mortality by an infectious disease, account for over 3 million deaths. The rate of infection is an estimated 8 million individuals per year, with 21,337 cases diagnosed in the United States in 1996 (CDC). Chemotherapy had great diminished the incidence of this disease in industrialized nations. The emergence of multidrug resistant strains of Mycobacterium tuberculosis and HIV-infected individuals with secondary infections of tuberculosis are having a worldwide impact on the epidemiology of these infectious agents. Mycobacteria possess remarkable intrinsic resistance to antimicrobial agents mediated by their unique cell wall composition. Treatment of tuberculosis requires the administration of multiple agents for months, which affects patient compliance, and ultimately the development of drug resistance. The CDC reports that greater than or equal to 75 percent of tuberculosis cases diagnosed in the United States (1996) were resistant to at least one drug. Combinatorial chemistry, in conjunction with high- throughput screening provides a new opportunity for drug discovery in this increasing important therapeutic area. A novel reporter assay for the identification of inhibitors of mycolic acid biosynthesis, an essential component of the mycobacterial cell wall has been developed. This assay will be used in a screen of an encoded combinatorial chemical collection, representing 1.6 million compounds. Proposed commercial applications: The goal of this research is the identification of novel antitubercular agents that act by inhibiting cell biosynthesis. A novel high-throughput assays has been development for screening large combinatorial chemical libraries comprising 1.6 million compounds. The development of a clinical, candidate resulting from the optimization of lead structures is the potential commercial application of this project.

结核病是全球由传染性疾病引起的死亡的主要原因。 疾病，占300多万人的死亡。感染率是一种 据估计，每年有800万人，其中21,337例被诊断为 美国在1996年(CDC)。化疗极大地降低了 这种疾病在工业化国家的发病率。新技术的出现 结核分枝杆菌多药耐药株与HIV感染 患有结核病继发感染的人有一种 对这些传染病病原体的流行病学产生了世界范围的影响。 分枝杆菌对抗菌药具有显著的内在耐药性 药物由其独特的细胞壁组成所介导。治疗 结核病需要在几个月内使用多种药物， 这会影响患者的依从性，并最终影响药物的开发 抵抗。疾控中心报告称，超过或等于75%的 在美国确诊的结核病病例(1996年)对 至少有一种药物。组合化学，结合高级化学。 吞吐量筛选为这一领域的药物发现提供了新的机会 增加重要治疗区域。一种新的报告分析方法 真菌酸生物合成抑制剂的鉴定--一种必不可少的 分枝杆菌细胞壁的成分已经被开发出来。这个化验 将在编码的组合化学集合的屏幕中使用， 代表了160万种化合物。 建议的商业应用： 本研究的目的是鉴定新型抗结核药物。 通过抑制细胞生物合成而起作用的药物。一种新型的高通量 用于筛选大型组合化学物质的分析方法已得到发展 包含160万个化合物的文库。一种临床应用的发展， 由引线结构优化产生的候选者是 该项目具有潜在的商业应用前景。