HIV-1 ENV PROTEINS--TARGETS FOR ANTIVIRAL CHEMOTHERAPY

HIV-1 ENV 蛋白——抗病毒化疗的靶点

• 批准号: 2091161
• 负责人: A ROBERT ROBERT NEURATH
• 金额: $ 26.08万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-11-07 至 1996-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2091161
• 关键词: AIDS; AIDS therapy; HIV envelope protein gp120; HIV envelope protein gp41; antiAIDS agent; chemical structure function; combination chemotherapy; cyanine; drug design /synthesis /production; drug resistance; drug screening /evaluation; human immunodeficiency virus 1; human tissue; lymphocyte; monocyte; porphyrins; tissue /cell culture; virus envelope

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.

1型人类免疫缺陷病毒复制中的任何步骤 (HIV-1) 可能作为抗病毒化疗的靶点。 因此，抗病毒药物可以针对 HIV-1 蛋白，这是 病毒复制，包括病毒结构蛋白和非结构蛋白 以及HIV-1调节基因的产物。 抗 HIV-1 化疗药物 针对 HIV-1 逆转录酶和蛋白酶的药物已成为 最广泛的调查。 努力开发保护性免疫原 抗 HIV-1 导致 env 糖蛋白区域的划分 gp12O 和 gp4l 对于感染至关重要。 这些地区包括： 位于 V3 高变环上的主要中和决定簇 gp12O； gp12O上包含CD4结合位点的结构域；融合 gp41 的结构域；和 gpl2O/gp4l 上参与寡聚化的位点 env 糖蛋白，即在病毒组装中。 这些功能上很重要 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，化合物抑制 V3 高变环与抗 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 淋巴细胞和早单核细胞系中的复制。 因此，一种快速预筛选具有抗 HIV-1 抗病毒作用的化合物的方法 基于放射免疫测定或酶联免疫吸附剂的活性 化验被发现。 大多数这些化合物抑制反应 来自不同 HIV-1 分离株（克隆）的 V3 环之间差异很大 一级氨基酸序列，以及相应的抗体。 这 拟议研究的目标是：（1）选择额外的抗病毒药物 对 V3 高变环具有特异性的化合物具有 (a) 高 对许多 HIV-1 分离株具有抗病毒活性，并且 (b) 细胞毒性低； (2) 化合物结构-功能关系的定义 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) 活动展示 这些化合物可对抗外周血中的原发性 HIV-1 分离株 淋巴细胞和单核细胞； (4) 具有反应基团的化合物的设计 导致它们与 HIV-1 糖蛋白不可逆结合，从而 增强抗病毒活性； (5)附加抗病毒药物的设计 靶向 HIV-1 包膜糖蛋白区域的化合物 V3循环； (6) 评估这些化合物的抗病毒活性 与针对 gpl2O/gp4l 以外位点的抗病毒药物联合使用， 例如，3'-叠氮基-2'-3'-二脱氧胸苷(AZT)； (7)就读于 更详细地了解这些化合物对 HIV-1 步骤的影响 复制； (8)寻找HIV-1耐药突变体的出现 上述化合物。 这些目标有望实现 改善联合治疗，并可能预防 HIV-1 感染。