DEVELOPMENT OF ANTI-HIV AGENTS

一种致细胞病变的逆转录病毒，人类免疫缺陷病毒（HIV）， 与致命性免疫抑制性 获得性免疫缺陷综合征（AIDS）。 病毒的复制依赖于RNA指导的DNA 聚合酶（逆转录酶; RT）。 其他HIV病毒基因 作为可能的药物靶点的产物包括内切核酸酶 (EN)和蛋白酶。 在该计划中，建议开发新的化合物， 相对于人选择性抑制HIV RT（α、β、γ） DNA聚合酶，从而提供了抗病毒的潜在基础 艾滋病前期患者的化疗。 两个这样的一般类 将合成以下化合物：1）新型焦磷酸盐（PP） 类似物; 2）衍生自PP组合的新型杂合药物 抑制剂（1）与核苷类HIV RT抑制剂（如AZT、ddT 和ddC）转化为单核苷酸， 抑制剂将被合成为潜在的前药。 此外，3） 非离子（烷基膦酸酯）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EN方面的进展密切相关 酶学和序列说明。 新的化合物将被仔细表征， 相关的化学和物理性质。 抑制剂的 将使用以下方法检测类别（1）和（2）的抑制活性： 纯化的HIV RT样品，我们还将测试RT抑制剂， 体外抗HIV活性。 结构/功能关系 相对于HIV RT绝对抑制测定， 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， Mg 2+与Mn 2+络合亲和力、空间位阻和其他 抑制剂的分子方面将与 RT的酶学数据，以阐明这些因素在 HIV RT抑制。 将评价类别（3）中的抑制剂 在特异性和对寡聚体的ID 50值依赖性方面 长度、膦酸酯结构和相关因素。 的 所获得的信息将用于发展合理设计的 有效治疗HIV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.