Inhibition of HIV-1 Maturation

HIV-1 成熟的抑制

• 批准号: 7592927
• 负责人: eric freed
• 金额: $ 32.3万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/7592927
• 关键词: Antiviral Agents; Betulinic Acid; Cells; Class; Cleaved cell; Collaborations; Endopeptidases; Event; Future; Gagging; Generations; HIV Drug Resistance Program; HIV-1; Individual; Mediating; Mutation; Numbers; Pathway interactions; Peptide Hydrolases; Pharmacologic Substance; Polyproteins; Process; Rate; Reporting; Resistance; Site; Site Visit; Variant; Virus; Work; gag Gene Products; inhibitor/antagonist; novel

The HIV-1 Gag proteins are synthesized as a polyprotein precursor, Pr55Gag, that is cleaved by protease (PR) during virus release from the infected cell. PR-mediated Pr55Gag processing follows a sequence of events that is kinetically controlled by the rate of processing at individual cleavage sites. Completion of the Gag processing cascade is essential for virus maturation and infectivity. In collaboration with Panacos Pharmaceuticals, we found that 3-0-(3-3-dimethyl-succinyl) betulinic acid (PA-457 or bevirimat) potently inhibits HIV-1 maturation by specifically blocking a late step in the Gag processing pathway. We have performed initial characterization of the mechanism of action of PA-457 and have isolated and characterized a number of PA-457-resistant HIV-1 variants. In ongoing and future studies, we will fully define the mechanism of action of PA-457 and in collaboration with Panacos will develop second-generation maturation inhibitors that may be active against both wild-type and PA-457-resistant HIV-1 isolates. [Corresponds to Freed Project 4 in the April 2007 site visit report of the HIV Drug Resistance Program]

HIV-1 GAG蛋白合成为多蛋白前体PR55GAG，在病毒从感染细胞释放过程中被蛋白酶（PR）裂解。 PR介导的PR55GAG处理遵循一系列事件，这些事件受单个切割位点的处理速率的动力学控制。完成插科打加工级联对于病毒的成熟和感染性至关重要。与Panacos Pharmaceuticals合作，我们发现3-0-（3-3-二甲基 - 核酸）β-甲酸（PA-457或bevirimat）有效地抑制了HIV-1的成熟，特异性阻止了GAG处理途径中的晚期。我们已经对PA-457的作用机理进行了初始表征，并隔离并表征了许多PA-457耐药的HIV-1变体。在正在进行的研究和未来的研究中，我们将充分定义PA-457的作用机理，并与Panacos合作将开发第二代成熟抑制剂，这些抑制剂可能对野生型和PA-457耐药HIV-1分离株有效。 [对应于2007年4月的《艾滋病毒抗药性计划的现场访问报告》中的释放项目4]