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

该合同支持美国国家过敏症和传染病研究所 疾病(NIAID)在其使命中刺激发现改进的 艾滋病相关机会性感染的治疗。虽然有一些药物 可用于治疗其中一些感染，更有效，也更少 毒性疗法是必要的。此外，公认的治疗方法并不存在。 用于某些机会性感染(OIS)。 体外试验和生化预筛选已被有效地用于 确定潜在新化合物的结构-活性关系(SAR) 治疗。基于生物化学的筛查测试可能特别有用 在发现抗OI药物方面因为：L)某些与艾滋病有关的药物 条件致病菌不能在体外培养，2)这样的检测是 对体外复制能力较差的病原体进行快速、高效的处理，3) 在某些病原体复制中起关键作用的酶 已识别并可用于治疗的类似宿主 可以确定可以同时用于评估的酶 选择性，以及5)大容量分析的发展允许详细的SAR 化合物的评估。这样的生化预筛选项目已经被 NIAID自1988年以来一直在运作，几种有希望的化合物 已确认身份。具体地说，化合物是从一种 自动数据库和叶酸酶抑制的评价 卡氏肺孢子虫、弓形虫及其宿主的代谢 哺乳动物组织。 这份合同的目的是继续努力筛选代理 复制所必需的代谢途径的酶分析 与艾滋病相关的机会性病原体。要解决的病原体包括 Carinii、弓形虫。和禽类分枝杆菌。

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.