Inhibition of HIV-1 Maturation

HIV-1 成熟的抑制

• 批准号: 8349153
• 负责人: eric freed
• 金额: $ 34.69万
• 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/8349153
• 关键词: Antiviral Agents; Betulinic Acid; Binding; Capsid; Capsid Proteins; Cells; Cleaved cell; Collaborations; Event; Gagging; HIV; HIV Drug Resistance Program; HIV-1; Individual; Mediating; Mutation; Pathway interactions; Pharmacologic Substance; Play; Polyproteins; Process; Reporting; Resistance; Role; SP1 gene; Site; Site Visit; Variant; Virus; Work; base; gag Gene Products; inhibitor/antagonist

The HIV-1 Gag proteins are synthesized as a polyprotein precursor, Pr55Gag, that is cleaved by 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'-dimethylsuccinyl) betulinic acid (PA-457 or bevirimat) potently inhibits HIV-1 maturation by specifically blocking a late step in the Gag processing pathway. We played a central role in defining the mechanism of action of bevirimat and have isolated and characterized a number of resistant HIV 1 variants. We are also investigating the target and mechanism of action of a compound (PF-46396) developed by Pfizer that is structurally distinct from bevirimat but like bevirimat blocks CA-SP1 processing. In ongoing studies, we are evaluating the antiviral activity of compounds that disrupt HIV-1 maturation by binding to the capsid protein. This work is being done in collaboration with Drs. A. Debnath and M. Summers. [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，在病毒从感染细胞释放期间被PR切割。PR介导的Pr 55 Gag加工遵循一系列事件，这些事件在动力学上由各个切割位点的加工速率控制。Gag加工级联的完成对于病毒成熟和感染性是必不可少的。在与Panacos Pharmaceuticals的合作中，我们发现3-0-（3 '-3'-二甲基琥珀酰基）桦木酸（PA-457或bevirimat）通过特异性阻断Gag加工途径中的晚期步骤来有效抑制HIV-1成熟。我们在确定bevirimat的作用机制方面发挥了核心作用，并分离和表征了许多耐药HIV 1变体。我们还在研究辉瑞公司开发的一种化合物（PF-46396）的作用靶点和机制，该化合物在结构上与贝韦瑞马特不同，但与贝韦瑞马特一样，可以阻断CA-SP1的加工。在正在进行的研究中，我们正在评估通过与衣壳蛋白结合来破坏HIV-1成熟的化合物的抗病毒活性。这项工作是与A博士合作进行的。Debnath和M.萨默斯 [对应于2007年4月艾滋病毒耐药性方案现场访问报告中的Freed项目4]