Design and Synthesis of HIV Integrase as Potential Anti-

作为潜在抗病毒药物的 HIV 整合酶的设计和合成

• 批准号: 7048193
• 负责人: TERRENCE BURKE
• 金额: --
• 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/7048193
• 关键词: AIDS therapy; HIV infections; X ray crystallography; acetylation; antiAIDS agent; antiviral agents; binding sites; chemical structure function; cytotoxicity; drug design /synthesis /production; enzyme inhibitors; enzyme substrate complex; human immunodeficiency virus 1; integrase; intermolecular interaction; ligands; mass spectrometry; virus DNA; virus protein

Inhibitors of HIV integrase (IN) are being developed as potential anti-AIDS drugs. One class of lead structure currently under investigation can be broadly characterized as being of the aryl beta-diketo family. Members of this class have been reported independently to exhibit potent inhibition of HIV integrase in extracellular enzyme assays and to provide good antiviral effects in HIV-infected cells. Through the systematic design and synthesis of a large number of aryl beta-diketo analogues, we have developed novel azido containing aryl beta-diketo variants, which exhibit high IN inhibitory potency in extracellular assays and provide antiviral effects cells with reduced cytotoxicity in HIV infected. Recent work has focused on replacement of the beta-diketo portion of our azido containing inhibitors with the naphthyridine pharmacophore, which has shown utility in other clinically-relevant HIV-1 integrase inhibitors. In order to elucidate the manner in which these and other inhibitors interact with IN DNA substrate complexes, chemical and photo-activatable affinity labels have been incorporated into high affinity inhibitors. We have also developed the first members of a novel, new class of pharmacological tool that function as "affinity acetylators" by site-specific acetylation of amino acid residues in the IN enzyme. Mass spectral studies are currently ongoing to elucidate sites of covalent attachment by these agents following incubation with the enzyme. Recent studies have examined the reactivities and selectivities towards the nucleophilic side chains of various amino acids of these affinity acetylators as compared with other alkylating functionalities. Based on differential reactivities, a new class of ?bifunctional? affinity ligands is being developed that may have applicability in the study of a broad range protein-ligand interactions. In separate studies, collaborative efforts are underway to obtain X ray structures of inhibitors bound to the HIV integrase enzyme. Information obtained from such X-ray structures should provide a starting point for the computer-assisted design of potent new inhibitors.

HIV整合酶（IN）的抑制剂正在发展为潜在的抗AID药物。目前正在研究的一类铅结构可以广泛地描述为芳基β-diketo家族。该类别的成员已独立报告，以表现出在细胞外酶测定中对HIV积分酶的有效抑制，并在HIV感染的细胞中提供良好的抗病毒作用。通过系统的设计和合成大量的芳基β-二基类似物，我们开发了含有芳基β-二甲虫变体的新颖的氮杂型，这些变体在细胞外测定中表现出较高的抑制效力，并提供了抗病毒效应细胞，并具有降低的HIV受感染细胞毒性感染的抗病毒效应。最近的工作集中在替换含有萘吡啶药丸的氮化剂抑制剂的β-二杆菌部分，该抑制剂已显示出在其他临床上与HIV-1集成酶抑制剂其他临床相关的效用。为了阐明这些和其他抑制剂与DNA底物复合物相互作用的方式，化学和光活化亲和力标签已纳入高亲和抑制剂中。我们还开发了一种新型新型药理学工具的第一批成员，该工具通过酶中氨基酸残基的位点特异性乙酰化作用为“亲和力乙酰剂”。与酶孵育后，目前正在进行质谱研究，以阐明这些药物的共价附着位点。最近的研究研究了与其他烷基化功能相比，这些亲和乙酰基各种氨基酸的核侧链的反应性和选择性。基于差异反应性，新的双功能？正在开发亲和力配体，可能在研究广泛的蛋白质 - 配体相互作用的研究中具有适用性。在单独的研究中，正在进行协作努力，以获取与HIV整合酶结合的抑制剂的X射线结构。从此类X射线结构获得的信息应为有效新抑制剂的计算机辅助设计提供一个起点。