DRUG TARGETS OF OPPORTUNISTIC PATHOGENS IN AIDS

艾滋病机会性病原体的药物靶点

• 批准号: 2065532
• 负责人: DANIEL V. SANTI
• 金额: $ 11.35万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-30 至 1994-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2065532
• 关键词: AIDS; alkyltransferase; antifungal agents; antiprotozoal agents; cooperative study; dihydrofolate reductase; drug design /synthesis /production; enzyme structure; opportunistic infections; thymidylate synthase

Despite advances in the therapy of opportunistic infections complicating AIDS, they remain a leading cause of morbidity and mortality. Testing of potential therapeutic agents is confounded by the difficulties in the cultivation of many of these pathogens and the unreliability of animal models in the testing of new agents. In order to circumvent these problems, we plan to clone enzymes which are targets for known classes of antibiotics, expressing these proteins in large quantities in heterologous systems (e.g. E. Coli and yeast), and characterizing the enzymologic parameters of the targets. The expressed proteins and their sequences will provide the basis for the three-dimensional structure determination and molecular modeling of the targets. The structural information will provide the basis for rational drug design and identification. Classes of compounds which have the structural components necessary to be new inhibitors will be tested for their efficacy in the in vitro inhibition of the targets. The organisms that have been chosen for study are Pneumocystis carinii, Cryptococcus neoformans, and Toxoplasma gondii. These organisms cause the bulk of life-threatening infections in patients with AIDS. Our group has experience with Pneumocystis carinii and Cryptococcus neoformans. Many of targets selected for this study have already been isolated and are ready for structural determination and molecular modeling. The other targets will rapidly be isolated given our experience in this field. The targets chosen are crucial enzymes in the folate and thymidylate biosynthetic pathways. Since agents which inhibit this pathway are already in clinical use for Pneumocystis carinii and Toxoplasma gondii, we know that these pathways are appropriate targets for chemotherapeutic intervention. The targets that have been selected are dihydrofolate reductase (DHFR; the target of trimethoprim), dihydropteroate synthetase (DHPS; the sulfonamide target), and thymidylate synthase (TS; the likely target of 5-fluorocytosine). Abundant kinetic structural information is available for two these enzymes (TS and DHFR), much of which has been determined by members of this group. Together the group provides a continuous system of drug development from cloning to expression to structural determination to molecular modeling. The group has demonstrated previous productive interactions. The drug targets in opportunistic pathogens will not be an entirely new venture, but an extension of on-going projects in these fields.

尽管在机会感染的治疗方面取得了进步 艾滋病，它们仍然是发病率和死亡率的主要原因。 测试 潜在的治疗剂被困难所困扰 培养许多这些病原体和动物的不可靠性 测试新代理的模型。 为了绕过这些 问题，我们计划克隆酶，这些酶是已知类别的目标 抗生素，在异源中大量表达这些蛋白质 系统（例如大肠杆菌和酵母），并表征酶学 目标的参数。 表达的蛋白质及其序列将 为三维结构确定提供基础 目标的分子建模。 结构信息将提供 理性药物设计和识别的基础。 类 具有新的结构成分的化合物 抑制剂将在体外抑制作用中测试其功效 目标。 已选择进行研究的生物是肺炎藻菌， 加密型新羊角和弓形虫Gondii。 这些生物会导致 艾滋病患者的大部分威胁生命的感染。 我们的小组有 具有肺炎雄细胞杆菌和加密赛的经验。 许多 为这项研究选择的目标已经隔离并准备就绪 用于结构测定和分子建模。 其他目标 考虑到我们在这一领域的经验，将迅速隔离。 选择的靶标是叶酸和胸腺胸酯中的关键酶 生物合成途径。 由于抑制此途径的代理已经已经 在用于肺炎和弓形虫弓形虫的临床用途中，我们知道 这些途径是化学治疗的合适靶标 干涉。 选择的目标是二氢叶酸 还原酶（DHFR；甲氧苄啶的靶标），二氢蛋白酶合成酶 （DHP；磺酰胺靶标）和胸苷酸合酶（TS；可能 5-氟细胞的靶标）。 大量的动力学结构信息是 可用于两种这些酶（TS和DHFR），其中大部分已经 由该组成员确定。 该小组共同提供了一个连续的药物开发系统 克隆至表达到分子建模的结构确定。 该小组已经证明了以前的生产互动。 药物 机会主义病原体中的目标不是全新的事业，而是 这些领域正在进行的项目的扩展。