STRUCTURAL STUDIES OF AIDS RESPONSIVE DRUGS

描述：(改编自申请者摘要)：卡氏肺孢子虫 (PC)是#年机会性感染和死亡的主要原因。 免疫抑制的个体，特别是艾滋病患者。抗叶酸 是迄今为止临床上最有效的抗前列腺癌药物，但他们的 使用受到毒性和抗药性问题的限制。个人电脑 二氢叶酸还原酶(DHFR)最近被克隆。它的亲和力 对于各种抗叶酸表明，抗菌药物，如 甲氧苄氨嘧啶和乙胺嘧啶是有效的抑制剂。 第二代抗癌剂等亲脂性抗叶酸酯 曲美曲辛和匹立克辛。据建议，这是由于具体的 Pc-DHFR与这些化合物的相互作用。 这一假说将通过比较晶体结构来检验 人和Pc DHFRs与辅因子NADPH和几种Pc-DHFRs的复合体 选择性抗叶酸。观察到的差异将被用来 基于结构的新型抗艾滋病佐剂抗叶酸酯的设计 由申请者及其合作者共同完成。

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.