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Pr 55 Gag，即 在病毒从感染细胞释放期间被蛋白酶（PR）裂解。PR介导的Pr 55 Gag 处理遵循一系列事件，这些事件在动力学上由 在单个切割位点加工。完成Gag处理级联至关重要 病毒的成熟和传染性。在与Panacos制药公司的合作中，我们发现 3-O-（3-3-二甲基-琥珀酰基）桦木酸（PA-457或bevirimat） 通过特异性阻断Gag加工的后期步骤，有效抑制HIV-1成熟 通路我们对PA-457的作用机制进行了初步表征， 已经分离并鉴定了许多抗PA-457的HIV-1变种。正在进行和 在未来的研究中，我们将全面定义PA-457的作用机制，并与合作伙伴合作， Panacos将开发第二代成熟抑制剂， 野生型和PA-457耐药HIV-1分离株。[对应于《自由项目4》， 2007年4月艾滋病毒耐药性项目现场访问报告]