DEVELOPMENT OF ANTI-HIV AGENTS

一种细胞病态逆转录病毒，人类免疫缺陷病毒(HIV) 与致命性免疫抑制的发病机制有关 这种疾病被称为获得性免疫缺陷综合症(AIDS)。 病毒的复制依赖于RNA引导的DNA 聚合酶(逆转录酶；RT)。其他HIV病毒基因 可能成为药物靶点的产品包括核酸内切酶 (EN)和一种蛋白酶。 在这项计划中，建议开发新的化合物， 选择性抑制相对于人类的HIV RT(阿尔法、贝塔、伽马) DNA聚合酶，为抗病毒提供了潜在的基础 艾滋病前患者的化疗。这类产品的两个一般类别 化合物将被合成：1)新型焦磷酸盐(PP) 类似物；2)PP组合衍生的新型杂交药物 含核苷HIV RT抑制剂(如AZT、DDT)的抑制剂(1) 和ddC)转化为单核苷酸，即活性的“掩蔽”衍生物 抑制剂将被合成为潜在的前药。此外，3) 非离子(烷基膦酸)寡核苷酸 序列将被合成为潜在的HIV EN抑制剂。这 方法将与小组在艾滋病毒防治方面的进展密切相关 酶学和序列规范。 新的化合物将被仔细地描述，并表示尊重 相关的化学和物理性质。抑制剂来自 将测试类别(1)和(2)的抑制活性 我们还将对HIV RT的纯化样本进行RT抑制剂测试 体外抗HIV活性。结构/功能关系将是 根据绝对HIV RT抑制和 病毒/宿主聚合酶抑制率作为模板的函数 和离子条件。酸碱性质的测定， 镁离子与锰离子的络合亲和力、空间位阻等 这些抑制剂的分子方面将与 关于RT的酶学数据来阐明这些因素在 HIV逆转录酶抑制。将对第(3)类抑制剂进行评估 在特异性和ID50值对齐聚物的依赖性方面 长度、磷酸盐结构及相关因素。这个 获得的信息将被用来进化合理的设计 有效治疗艾滋病毒感染的化合物。

A cytopathic retrovirus, human immunodeficiency virus (HIV) has been linked to pathogenesis of the fatal immunosuppressive disease known as Acquired Immune Deficiency Syndrome (AIDS). Replication of the virus is dependent on an RNA-directed DNA polymerase (reverse transcriptase; RT). Other HIV viral gene products that are possible drug targets include an endonuclease (EN) and a protease. In this program it is proposed to develop new compounds that selectively inhibit HIV RT relative to human (alpha, beta, gamma) DNA polymerases, thus providing a potential basis for anti-viral chemotherapy of pre-AIDS patients. Two general classes of such compounds will be synthesized: 1) novel pyrophosphate (PP) analogs; 2) novel hybrid drugs derived from combination of PP inhibitors (1) with nucleoside HIV RT inhibitors (such as AZT, ddT and ddC) into a single nucleotide, 'Masked' derivatives of active inhibitors will be synthesized as potential prodrugs. In addition, 3) nonionic (alkylphosphonate) oligonucleotides with defined sequence will be synthesized as potential HIV EN inhibitors. This approach will be closely linked to group progress on HIV EN enzymology and sequence specification. The new compounds will be carefully characterized with respect to relevant chemical and physical properties. Inhibitors from categories (1) and (2) will be tested for inhibitory activity using purified samples of HIV RT we will also test RT inhibitors for anti-HIV activity in vitro. Structure/function relationships will be determined with respect to absolute HIV RT inhibition and virus/host polymerase inhibition ratios as a function of template and ionic conditions. Determination of acid-base properties, Mg2+ vs. Mn2+ complexation affinities, steric, and other molecular aspects of the inhibitors will be compared with enzymological data on RT to elucidate the role of these factors in HIV RT inhibition. Inhibitors from category (3) will be evaluated in terms of specificity and ID50 value dependence on oligomer length, phosphonate structure, and related factors. The information obtained will be used to evolve rationally designed compounds effective in the treatment of HIV infections.