BIOCHEM.SCREENS FOR AGENTS EFF. AGAINST AIDS-RELATED OIS

该合同支持国家过敏和传染病研究所 疾病（NIAID）在其使命，以刺激发现改善 治疗艾滋病相关的机会性感染。 一些药物 可用于治疗其中一些感染，更有效， 需要毒性治疗。 此外，不存在公认的治疗方法， 机会性感染（OIs）。 体外试验和生化预筛选已被有效地用于 确定潜在新化合物结构-活性关系（SAR） 治疗 基于生物化学的筛选测试可能特别有用 在抗OI药物的发现，因为：1）某些艾滋病相关的 机会致病菌不能在体外培养，2）这种测定法 快速，对体外复制较差的病原体更有效，3） 在某些病原体复制中起关键作用的酶已经被 已鉴定并可用于治疗，4）类似宿主 可以鉴定出可用于同时评价 选择性，5）高容量检测的发展允许详细的SAR 化合物的评价。这样一个生化预筛选项目， 自1988年以来，NIAID一直在运作， 鉴定 具体地说，化合物是从一个合理的选择， 自动化数据库和评价叶酸酶的抑制 卡氏肺孢子虫、刚地弓形虫和宿主分离的代谢物 哺乳动物组织 本合同的目的是继续努力筛选代理人， 酶法测定复制的代谢途径 艾滋病相关的机会致病菌。 要解决的病原体包括 P. carinii、刚地木霉（T. gondii.）和鸟分枝杆菌。

This contract supports the National Institute of Allergy and Infectious Diseases (NIAID) in its mission to stimulate the discovery of improved therapies of AIDS-associated opportunistic infections. While a few drugs are available to treat some of these infections, more efficacious and less toxic therapies are needed. Additionally, accepted therapies do not exist for certain opportunistic infections (OIs). In vitro assays and biochemical prescreening have been used effectively to identify structure-activity relationships (SAR) of potential new therapies. Biochemically based screening tests may be particularly useful in discovery of anti-OI drugs because: l) certain AIDS-related opportunistic pathogens cannot be cultured in vitro, 2) such assays are rapid, and more efficient for pathogens that replicate poorly in vitro, 3) enzymes critical in the replication of certain pathogens have been identified and may be exploitable therapeutically, 4) analogous host enzymes may be identified that could be used to simultaneously evaluate selectivity, and 5) development of high volume assays permits detailed SAR evaluations of compounds. Such a biochemical prescreening project has been operational at NIAID since 1988 and several promising compounds have been identified. Specifically, compounds were rationally selected from an automated data base and evaluated for inhibition of enzymes of folic acid metabolism isolated from Pneumocystis carinii, Toxoplasma gondii and host mammalian tissues. The purpose of this contract is to continue efforts to screen agents in enzymatic assays of metabolic pathways essential to the replication of AIDS-related opportunistic pathogens. Pathogens to be addressed include P. carinii, T.gondii. and Mycobacterium avium.