STRUCTURAL STUDIES OF AIDS RESPONSIVE DRUGS

艾滋病反应药物的结构研究

• 批准号: 2190355
• 负责人: Vivian Cody
• 金额: $ 17.53万
• 依托单位: HAUPTMAN-WOODWARD MEDICAL RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2190355
• 关键词: AIDS; NAD(H) phosphate; Pneumocystis carinii; Pneumocystis pneumonia; X ray crystallography; antiAIDS agent; chemical structure function; computer simulation; dihydrofolate reductase; drug screening /evaluation; opportunistic infections

DESCRIPTION: (Adapted from Applicant's abstract): Pneumocystis carinii (Pc) is a major cause of opportunistic infection and mortality in immunosuppressed individuals, particularly those with AIDS. Antifolates have been the clinically most effective anti-Pc agents to date but their use has been limited by problems of toxicity and resistance. Pc dihydrofolate reductase (DHFR) has been recently cloned. Its affinity for various antifolates indicates that antibacterials such as trimethoprim and pyrimethamine are affective inhibitors as are lipophilic antifolates such as the second generation anticancer agents trimetrexate and piritrexim. This, it is proposed, is due to specific interactions of Pc DHFR with these compounds. This hypothesis will be tested by comparing the crystal structures of human and Pc DHFRs in complex with the cofactor NADPH and several Pc- selective antifolates. The observed differences will be exploited for structure-based design of new antifolates for use as anti-AIDS adjuvants by the applicant together with her collaborators.

描述：（改编自申请人的摘要）：卡氏肺囊虫 (PC) 是机会性感染和死亡的主要原因 免疫抑制个体，特别是艾滋病患者。抗叶酸剂 是迄今为止临床上最有效的抗 PC 药物，但它们 由于毒性和耐药性问题，其使用受到限制。个人电脑 二氢叶酸还原酶（DHFR）最近已被克隆。 其亲和力 对于各种抗叶酸剂表明抗菌剂，例如 甲氧苄啶和乙胺嘧啶都是情感抑制剂 亲脂性抗叶酸剂，例如第二代抗癌剂 三甲曲沙和吡曲辛。据建议，这是由于特定 Pc DHFR 与这些化合物的相互作用。 该假设将通过比较晶体结构来检验 人类和 Pc DHFR 与辅因子 NADPH 和多种 Pc- 形成复合物 选择性抗叶酸剂。观察到的差异将被用于 用作抗艾滋病佐剂的新型抗叶酸剂的基于结构的设计 由申请人及其合作者共同提出。