STRUCTURAL STUDIES OF AIDS RESPONSIVE DRUGS

描述：（改编自申请人摘要）：卡氏肺孢子虫 (Pc)是导致机会性感染和死亡的主要原因， 免疫抑制者，特别是艾滋病患者。抗叶酸 是迄今为止临床上最有效的抗Pc剂， 但其使用受到毒性和抗性问题的限制。PC 二氢叶酸还原酶（DHFR）最近已被克隆。 其亲和力 各种抗叶酸剂表明， 甲氧苄啶和乙胺嘧啶是有效的抑制剂， 亲脂性抗叶酸剂如第二代抗癌剂 曲美曲嗪和吡曲辛。这是因为，具体的 Pc DHFR与这些化合物的相互作用。 这一假设将通过比较以下晶体结构来检验： 人和Pc DHFR与辅因子NADPH和几种Pc- 选择性抗叶酸剂观察到的差异将被用于 基于结构设计用作抗艾滋病佐剂的新抗叶酸剂 申请人及其合作者。

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.