Inhibition of HIV-1 Maturation

HIV-1 成熟的抑制

• 批准号: 8763211
• 负责人: eric freed
• 金额: $ 31.69万
• 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/8763211
• 关键词: Betulinic Acid; Binding; Binding Sites; Capsid; Cells; Cleaved cell; Collaborations; Development; Drug Addiction; Drug resistance; Employee Strikes; Gagging; HIV Drug Resistance Program; HIV-1; Mutation; Pathway interactions; Peptide Hydrolases; Pharmacologic Substance; Polyproteins; Process; Reporting; Resistance; SP1 gene; Site Visit; Structure; Viral; Virus; Work; base; gag Gene Products; inhibitor/antagonist; mutant; novel; structural biology

The HIV-1 Gag proteins are synthesized as a polyprotein precursor, Pr55Gag, that is cleaved by the viral protease during virus release from the infected cell. 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, the conversion of capsid-SP1 (CA-SP1) intermediate to mature CA. We identified the target of this compound by selecting for and characterizing a panel of drug-resistant mutants. Furthermore, we have recently initiated studies on a structurally distinct compound discovered by Pfizer that also blocks CA-SP1 processing and have identified a partially overlapping panel of resistant mutants. Some of the resistant mutants are highly assembly defective in the absence of the inhibitor and display a striking degree of drug dependence. Efforts are underway to understand the mechanistic basis for maturation inhibitor binding and activity. We hypothesize that defining the structure of the maturation inhibitor binding site(s) will greatly facilitate the development of novel and more potent inhibitors; to this end, we are collaborating with structural biology labs. Finally, we are collaborating with Drs. A. Debnath and M. Summers to define compounds that block maturation by targeting CA. Finally, we are involved in studies aimed at developing derivatives of bevirimat that display greater potency and broader activity against polymorphic isolates of HIV-1. [Corresponds to Freed Project 3 in the October 2011 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病毒蛋白酶切割。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加工途径中的后期步骤，capture-SP1（CA-SP1）中间体向成熟CA的转化，有效地抑制HIV-1成熟。我们通过选择和表征一组耐药突变体来确定这种化合物的靶点。此外，我们最近启动了对辉瑞发现的一种结构独特的化合物的研究，该化合物也阻断了CA-SP1的加工，并确定了一组部分重叠的耐药突变体。一些耐药突变体在没有抑制剂的情况下是高度组装缺陷的，并且显示出惊人程度的药物依赖性。正在努力了解成熟抑制剂结合和活性的机制基础。我们假设定义成熟抑制剂结合位点的结构将极大地促进新型和更有效的抑制剂的开发;为此，我们正在与结构生物学实验室合作。最后，我们与A博士合作。Debnath和M. Summers定义通过靶向CA阻断成熟的化合物。最后，我们参与了旨在开发贝韦瑞马特衍生物的研究，这些衍生物对HIV-1的多态性分离株表现出更大的效力和更广泛的活性。[对应于2011年10月艾滋病毒耐药性项目现场访问报告中的Freed项目3]