HIV-1 ENV PROTEINS--TARGETS FOR ANTIVIRAL CHEMOTHERAPY

人类免疫缺陷病毒1型复制的任何步骤 （HIV-1）可能成为抗病毒化疗的靶点。 因此，抗病毒剂可以针对HIV-1蛋白质， 病毒复制，包括病毒结构和非结构蛋白 和HIV-1调节基因的产物。 抗HIV-1化疗药物 靶向HIV-1逆转录酶和蛋白酶的药物一直是 最广泛的调查。 开发保护性免疫原的努力 针对HIV-1的抗体导致了对env糖蛋白区域的描绘 gp 120和gp 41对感染至关重要。 这些地区包括： 位于V3高变环上的主要中和决定簇 gp 120上包含CD 4结合位点的结构域; gp 41的结构域;以及gp 120/gp 41上参与 env糖蛋白，即，在病毒装配中。 这些功能重要 可被具有适当特异性的抗体识别的位点代表 也是化疗的潜在靶点。 事实上，抑制 V3高变环和抗V3特异性抗体之间的反应 发现了抗体。 大多数（约67%）物质 抑制这种抗原-抗体相互作用也抑制了 HIV-1在T淋巴细胞和前单核细胞系中的复制。 因此，提供了一种用于具有抗HIV-1抗病毒活性的化合物的快速预筛选方法， 基于放射免疫测定或酶联免疫吸附剂的活性 检测发现。 这些化合物中的大多数抑制反应 来自不同HIV-1分离株（克隆）的V3环之间， 在一级氨基酸序列中，以及相应的抗体。 的 本研究的目的是：（1）筛选新的抗病毒药物， 特异于V3高变环的化合物，其具有（a）高 对许多HIV-1分离株的抗病毒活性，和（B）低细胞毒性; (2)定义化合物的结构-功能关系， 针对V3环的抗病毒活性，导致合理的 设计具有改进活性的药物;（3）证明 这些化合物针对外周血中的主要HIV-1分离株 淋巴细胞和单核细胞;（4）设计具有反应性基团的化合物 导致它们与HIV-1糖蛋白的不可逆结合， 抗病毒活性的增强;（5）额外的抗病毒药物的设计 靶向HIV-1包膜糖蛋白区域的化合物， V3环;（6）当存在V3环时，这些化合物的抗病毒活性的评估。 与靶向gp 120/gp 41以外的位点的抗病毒药物组合， 例如，3 '-叠氮基-2'-3 '-双脱氧胸苷（AZT）;（7）研究 更详细地说明这些化合物对HIV-1中步骤的影响 （8）寻找对HIV-1耐药的突变体; 上述化合物。 预计这些目标将实现 从而改进联合治疗，并可能预防HIV-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.