HIV-PROTEASE INHIBITORS AND ANTIBIOTICS AS ANTIVIRALS

HIV 蛋白酶抑制剂和抗生素作为抗病毒药

• 批准号: 3770417
• 负责人: M P SELVAM
• 金额: --
• 依托单位: BUREAU OF HEALTH PLANNING AND RESOURCES DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3770417
• 关键词: amphotericin B; antiAIDS agent; antiviral agents; drug adverse effect; drug screening /evaluation; drug vehicle; foscarnet; haloperidol; human immunodeficiency virus 1; immunofluorescence technique; liposomes; macrolide antibiotics; nystatin; protease inhibitor; radiotracer; reverse transcriptase inhibitors; synthetic peptide; tissue /cell culture; virus antigen; virus protein; virus replication; western blottings; zidovudine

Nystatin-A was compared with Amphotericin-B, AZT and foscarnet for their respective abilities to inhibit the replication of human immunodeficiency virus (HIV-1) in H9 cells. Nystatin-A and Amphotericin-B are polyene macrolide antibiotics. Foscarnet, a trisodium phosphonoformate and AZT are the inhibitors of reverse transcriptase (RT). HIV-1 infected H9 cells were cultured for seven days in the presence of all these drugs,at various concentrations and RT activity and p24 antigen production were quantitated. Untreated, HIV-1 infected H9 cells served as controls. Nystatin-A inhibited viral replication most effectively at 10 microg/ml, a concentration that did not affect cell viability. Nystatin-A treatment inhibited RT activity by 95% and p24 production by 90%. These levels of inhibition were comparable to that mediated by Amphotericin B AZT and foscarnet. Western blot analysis of the HIV-infected H9 cells treated with these drugs did not detect any viral protein at the cellular level. These findings were further corroborated by indirect immunofluorescence studies using monoclonal anti-gp120 FITC-conjugated antibodies, and by polymerase chain reaction analysis using a 32P-labeled probe. These results suggest that Nystatin-A merits attention as an antiviral drug for the treatment of HIV-1 infection. In-vivo drug delivery by liposome encapsulation is currently under study. Cerulenin, an inhibitor of fatty acid and sterol synthesis, has been shown to inhibit the HIV replication in H9 cells by 50%. Cerulenin was highly toxic to cells even at 2 ug/ml concentration. The synthetic peptide analog of HIV-protease, SKF-108922 was also shown to have an inhibitory effect on HIV-replication. Both of these agents will be incorporated in to immunoliposomes and future experiments will focus on delivering these agents with greater specificity to reduce toxicity. Haldol, (haloperidol) a closely related compound and known antipsychotic agent, was chosen for testing. Haloperidol inhibits the HIV-1 and HIV-2 proteases in a concentration dependent manner.

比较了Nystatin-A与两性霉素B、AZT和膦甲酸的 各自抑制人类免疫缺陷复制的能力 H9细胞中的HIV-1。 制霉菌素A和两性霉素B是多烯 大环内酯类抗生素。膦甲酸三钠和AZT是 逆转录酶（RT）抑制剂。 HIV-1感染的H9细胞 在所有这些药物的存在下培养7天， 定量浓度和RT活性和p24抗原产生。 未处理的HIV-1感染的H9细胞作为对照。 制霉菌素A 在10微克/毫升时，抑制病毒复制最有效， 浓度不影响细胞活力。 制霉菌素A治疗 RT活性抑制95%，p24产生抑制90%。 这些水平的 抑制作用与两性霉素B AZT和 膦甲酸。用免疫印迹法分析经抗HIV抗体处理的HIV感染的H9细胞的免疫印迹结果。 这些药物在细胞水平上没有检测到任何病毒蛋白。 这些 间接免疫荧光研究进一步证实了这些发现 使用单克隆抗gp 120 FITC-偶联抗体，并通过聚合酶 使用32 P标记的探针进行链式反应分析。 这些结果表明 Nystatin-A作为一种抗病毒药物值得关注， HIV-1感染。 通过脂质体包封的体内药物递送是 目前正在研究中。 脂肪酸和甾醇抑制剂浅蓝菌素 合成，已显示通过以下方式抑制H9细胞中的HIV复制： 百分之五十 浅蓝菌素即使在2 μ g/ml浓度下对细胞也具有高度毒性。 HIV蛋白酶的合成肽类似物SKF-108922也显示出 对HIV复制有抑制作用。 这两名探员 免疫脂质体，未来的实验将集中在 以更高的特异性递送这些药剂以降低毒性。 氟哌啶醇，（氟哌啶醇）一种密切相关的化合物和已知的抗精神病药 被选中进行测试。 氟哌啶醇抑制HIV-1和HIV-2 蛋白酶以浓度依赖性方式。