HIV-1 ENV PROTEINS--TARGETS FOR ANTIVIRAL CHEMOTHERAPY

复制人类免疫缺陷病毒1型的任何步骤 (HIV-1)可能成为抗病毒化疗的目标。 因此，抗病毒药物可以针对HIV-1蛋白质，这些蛋白质对 病毒复制，包括病毒结构蛋白和非结构蛋白 以及HIV-1调控基因的产物。抗HIV-1化疗 针对HIV-1逆转录酶和蛋白酶的药物一直是 最广泛的调查。努力开发保护性免疫原 抗HIV-1导致包膜糖蛋白区域的描绘 Gp20和gp41对感染起关键作用。这些地区包括： 位于V3高变量环上的主中和行列式 Gpl2O的；gpl2O上包含c4结合位点的结构域；融合 Gp41的结构域；以及gpl2O/gp41上参与齐聚的位点 包膜糖蛋白，即在病毒组装中。这些在功能上很重要 可由具有适当特异性的抗体识别的部位代表 也是化疗的潜在目标。事实上，化合物抑制作用 V3高变环与抗V3特异性抗体的反应 抗体被发现了。大多数物质(约67%) 抑制这种抗原-抗体相互作用也会抑制 HIV-1在T淋巴细胞和原单核细胞系中的复制 因此，一种抗HIV-1抗病毒化合物的快速预筛选方法 基于放射免疫分析或酶联免疫吸附剂的活性 发现了化验方法。这些化合物中的大多数都抑制了反应。 来自不同HIV-1分离株(克隆)的V3环之间，差异很大 在初级氨基酸序列中，以及相应的抗体。这个 拟议研究的目标是：(1)选择更多的抗病毒药物 具有(A)高的V3高变量环特有的化合物 对许多HIV-1分离株的抗病毒活性，以及(B)低细胞毒性； (2)化合物的结构-功能关系定义 针对V3环的抗病毒活性，导致理性 提高活性的药物设计；(3)活性演示 这些化合物对外周血中主要HIV-1分离株的作用 淋巴细胞和单核细胞；(4)具有活性基团的化合物的设计 导致它们不可逆地与HIV-1糖蛋白结合，从而 增强抗病毒活性；(5)附加抗病毒药物的设计 针对HIV-1包膜糖蛋白区域的化合物 V3环；(6)评估这些化合物的抗病毒活性 结合靶向gpl2O/gp41以外的位点的抗病毒药物， 例如，3‘-叠氮-2’-3‘-二脱氧胸苷(AZT)；(7)研究 更详细的这些化合物对HIV-1中步骤的影响 复制；(8)寻找出现抗药性的HIV-1突变体 上述化合物。这些目标是可望实现的 导致改进综合治疗，并可能预防艾滋病毒-1 感染。

Any step in replication of the human immunodeficiency virus type 1 (HIV-1) could potentially serve as a target for antiviral chemotherapy. Thus, antiviral agents could be aimed at HIV-1 proteins essential for virus replication, including viral structural and non-structural proteins and products of HIV-1 regulatory genes. Anti-HIV-1 chemotherapeutic agents targeted to HIV-1 reverse transcriptase and protease have been the most extensively investigated. Efforts to develop protective immunogens against HIV-1 resulted in the delineation of regions on env glycoproteins gpl2O and gp4l critical for infection. These regions include: the principal neutralizing determinant located on the V3 hypervariable loop of gpl2O; domains on gpl2O comprising the CD4 binding site; the fusion domain of gp41; and sites on gpl2O/gp4l involved in oligomerization of env glycoproteins, i.e., in virus assembly. These functionally important sites, recognizable by antibodies with appropriate specificity, represent also potential targets for chemotherapy. Indeed, compounds inhibiting the reaction between the V3 hypervariable loop and anti-V3 specific antibodies were discovered. The majority (about 67%) of substances inhibiting this antigen-antibody interaction also inhibited the replication of HIV-1 in both T-lymphocytic and promonocytic cell lines. Thus, a rapid prescreening method for compounds with anti-HIV-1 antiviral activity based on radioimmunoassays or enzyme-linked immunoadsorbent assays was discovered. Most of these compounds inhibited the reaction between V3 loops from distinct HIV-1 isolates (clones), differing greatly in primary amino acid sequence, and the corresponding antibodies. The goals of the proposed research are: (1) selection of additional antiviral compounds specific for the V3 hypervariable loop having (a) high antiviral activity against many HIV-1 isolates, and (b) low cytotoxicity; (2) Definition of structure-function relationships for compounds with antiviral activity directed against V3 loops, leading to the rational design of drugs with improved activity; (3) Demonstration of activity of these compounds against primary HIV-1 isolates in peripheral blood lymphocytes and monocytes; (4) Design of compounds with reactive groups leading to their irreversible binding to HIV-1 glycoproteins and thus to potentiation of antiviral activity; (5) Design of additional antiviral compounds targeted to regions on HIV-1 envelope glycoproteins other than the V3 loop; (6) Assessment of antiviral activity of these compounds when combined with antiviral drugs targeted to sites other than gpl2O/gp4l, for example, 3'-azido-2'-3'-dideoxythymidine (AZT); (7)To study in greater detail the effect of these compounds on steps in HIV-1 replication; (8) Search for the emergence of HIV-1 mutants resistant to the aforementioned compounds. Accomplishment of these goals is expected to lead to improved combined therapy, and possibly prophylaxis of HIV-1 infections.