AGENTS AGAINST TOXOPLASMA AND PNEUMOCYSTIS

抗弓形虫和肺孢子虫的药物

• 批准号: 2390435
• 负责人: JAMES R. PIPER
• 金额: $ 27.75万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2390435
• 关键词: AIDS; Pneumocystis carinii; Pneumocystis pneumonia; Toxoplasma gondii; X ray crystallography; antiprotozoal agents; dihydrofolate reductase; drug design /synthesis /production; enzyme inhibitors; infectious encephalitis; laboratory mouse; opportunistic infections; pharmacokinetics; tissue /cell culture

DESCRIPTION (Adapted from Applicant's Abstract). The goal of the proposed research is the identification of improved agents for the treatment of toxoplasmic encephalitis and Pneumocystis (P) carinii pneumonia which result from opportunistic infections in patients with AIDS and other immunosuppressive disorders. Specifically, agents that inhibit the function of dihydrofolate reductase (DHFR), an enzyme vital to Toxoplasma (T) gondii and P. carinii, will be identified. Another aim is to design more effective and selective lipophilic antifolates using structure- activity relationships gained from a current project (U01 AI30279, expiration date June 30, 1995) as well as crystal structure-based methods. In their current work, these investigators have identified several agents active against both T. gondii and P. carinii DHFR, some of which are also active against T. gondii in culture, and even though they are analogous with non-selective trimetrexate and piritrexim, these compounds have significant selectivity toward the pathogenic DHFRs over mammalian DHFR. The active and selective lipophilic antifolates feature a ,4-diamino- 5-methyl -5-deazapteridin-6-yl group attached through a two-atom bridge (-CH2NR-, -CH2S-, -CH2CH2-) to a side chain conferring lipophilicity. The investigators now propose to combine the best features of the side chains and bridges to produce improved agents while simultaneously determining the crystal structures of some of their current inhibitors complexed to human and P. carinii DHFR. Information gained from these comparative structural studies will be incorporated into the design of more selective and potent lipophilic antifolates against P. carinii. Preliminary crystallographic results have also suggested three different modifications of trimethoprim which would be expected to increase its selectivity toward P. carinii DHFR. To test these hypotheses, trimethoprim analogues will be synthesized for evaluation, and their crystal structures will be determined. Antifolate candidates synthesized under this project will be evaluated for efficacy by Dr. Sherry F. Queener of Indiana University Medical School under a subcontractural agreement and also by other laboratories supported by contracts with NIAID. The compounds will be tested in a two-part primary evaluation for (a) their inhibitory effect against DHFR from both T. gondii and P. carinii and also from a mammalian source (rat liver), and (b) their ability to inhibit growth of the pathogenic organisms in culture. Agents whose primary screening results show them to warrant further study will be tested in mice infected with both T. gondii and P. carinii.

描述（改编自申请人的摘要）。拟议的目标 研究是确定治疗的改进药物 弓形虫脑炎和卡氏肺孢子虫肺炎 艾滋病和其他疾病患者的机会性感染所致 免疫抑制疾病。 具体而言，抑制 二氢叶酸还原酶 (DHFR) 的功能，这是一种对弓形虫至关重要的酶 (T) 弓形虫和 P. carinii，将被识别。 另一个目的是设计 使用结构更有效和选择性的亲脂性抗叶酸剂 从当前项目中获得的活动关系（U01 AI30279， 有效期 1995 年 6 月 30 日）以及基于晶体结构的 方法。 在他们目前的工作中，这些研究人员已经确定 几种对弓形虫和卡氏疟原虫均具有活性的药物 DHFR，一些 其中在培养物中也对弓形虫具有活性，尽管 它们与非选择性三甲曲沙和吡曲辛类似，这些 化合物对致病性 DHFR 具有显着的选择性 哺乳动物 DHFR。 活性和选择性亲脂性抗叶酸剂的特点 ,4-二氨基-5-甲基-5-去氮蝶啶-6-基通过 与侧链的双原子桥（-CH2NR-、-CH2S-、-CH2CH2-） 亲脂性。研究人员现在建议结合最好的功能 侧链和桥以生产改进的试剂，同时 同时测定某些物质的晶体结构 目前的抑制剂与人和 P. carinii DHFR 复合。 信息 从这些比较结构研究中获得的成果将被纳入 设计更具选择性和更有效的亲脂性抗叶酸剂 对抗 P. carinii。初步的晶体学结果也 建议对甲氧苄啶进行三种不同的修饰，其中 预计会增加其对 P. carinii DHFR 的选择性。测试 根据这些假设，将合成甲氧苄啶类似物 评估，并确定它们的晶体结构。抗叶酸剂 将评估该项目下合成的候选药物的功效 由印第安纳大学医学院的 Sherry F. Queener 博士在 分包协议以及其他实验室支持的 与 NIAID 签订合同。 这些化合物将分两部分进行初步测试 评估 (a) 它们对两种 T 的 DHFR 的抑制作用。 弓形虫和卡氏弓形虫，也来自哺乳动物来源（大鼠肝脏），以及 (b) 它们抑制病原微生物生长的能力 文化。 初步筛选结果表明他们有资格的代理人 进一步的研究将在感染弓形虫和弓形虫的小鼠中进行测试。 卡里尼。