DESIGN AND SYNTHESIS OF NONPEPTIDE PROTEASE INHIBITORS

非肽蛋白酶抑制剂的设计与合成

• 批准号: 7922372
• 负责人: ARUN K GHOSH
• 金额: $ 21.32万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922372
• 关键词: AIDS chemotherapy; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Amines; Anti-HIV Agents; Antiviral Agents; Binding; Biological; Biological Assay; Biological Availability; Caco-2 Cells; Cells; Clinical; Collaborations; Combined Modality Therapy; Crystallography; Development; Drug Design; Drug Kinetics; Drug resistance; Enzyme Inhibition; Exhibits; FDA approved; Future; Generations; HIV; HIV Protease; HIV Protease Inhibitors; HIV drug resistance; HIV-1; HIV-1 protease; Highly Active Antiretroviral Therapy; Laboratories; Letters; Ligands; Metabolic; Molecular; Molecular Models; Multi-Drug Resistance; Names; Oral; Organic Synthesis; Outcome; Patients; Peptide Hydrolases; Peptides; Performance; Pharmaceutical Preparations; Property; Protease Inhibitor; Proteins; Quality of life; Research; Research Personnel; Resistance; Resistance profile; Resolution; Reverse Transcriptase Inhibitors; Roentgen Rays; Solubility; Structure; Time; Toxic effect; Treatment Protocols; Uncertainty; Variant; Viral Drug Resistance; Virus; Work; absorption; aqueous; base; combat; design; effective therapy; experience; improved; inhibitor/antagonist; insight; molecular modeling; mortality; multidisciplinary; mutant; next generation; novel; pill; programs; resistant strain; scaffold; small molecule; tetrahydrofuran; therapy resistant; tool

DESCRIPTION (provided by applicant): The incorporation of HIV-1 protease inhibitors (PIs) in 1996 into combination therapy regimens with two or more reverse transcriptase inhibitors has been critical to the reduction of AIDS related mortality, improvement of quality of life, and enhancement of HIV/AIDS management. Highly active antiretroviral therapy (HAART) remains the most effective treatment option for HIV/AIDS, but there are many serious limitations of current treatment regimens. The emergence of multidrug-resistant HIV-1 variants is perhaps, one of the most formidable challenges. In our continuing collaborative research efforts toward developing new generations of protease inhibitors, our structure-based design strategies have led to the design and discovery of protease inhibitor UIC-94017 (later named TMC-114, or darunavir). Darunavir has exhibited marked antiviral activity, excellent drug resistance profiles against multidrug-resistant strains and favorable pharmacokinetic properties. On June 23, 2006, darunavir was approved by the FDA as the first treatment for drug-resistant HIV. Darunavir represents the first of a new generation of inhibitors to combat drug-resistant HIV. However, it is far from ideal for long-term effective treatment. Issues concerning oral bioavailability, pill-burden and possible emergence of resistance over time remain to be answered. Based upon our high resolution X-ray crystal structures of darunavir-bound HIV protease and a number of other protein-ligand structures, we have envisioned a number of intriguing design concepts and developed tools to combat drug-resistance. We have carried out preliminary structure-activity studies and generated a number of small molecule leads. This work now forms the basis of our proposed studies which include: (a) structure-based design and synthesis of bis-THF-derived and nonsulfonamide-based novel drug-like PIs; (b) design and development of novel ligands and scaffolds to improve pharmacological profiles of cyclopentyl-tetrahydrofuran (cp-THF)-derived PIs; (c) structure-based design and development of novel templates, scaffolds and heterocyclic ligands to generate novel small molecule drug-like PIs; (d) performance of in-depth drug-resistance studies and determination of X-ray structures of selected inhibitors to gain molecular insight. This research integrates organic synthesis, protein-ligand x-ray crystallography, molecular modeling and in-depth virus and cell-biological studies to design the next generation of HIV-1 protease inhibitors.

描述（由申请人提供）：1996年将HIV-1蛋白酶抑制剂（pi）纳入两种或两种以上逆转录酶抑制剂的联合治疗方案中，对降低艾滋病相关死亡率、改善生活质量和加强艾滋病毒/艾滋病管理至关重要。高效抗逆转录病毒疗法（HAART）仍然是艾滋病毒/艾滋病最有效的治疗选择，但目前的治疗方案存在许多严重的局限性。耐多药HIV-1变种的出现可能是最艰巨的挑战之一。在开发新一代蛋白酶抑制剂的持续合作研究中，我们基于结构的设计策略导致了蛋白酶抑制剂UIC-94017（后来被命名为TMC-114，或darunavir）的设计和发现。Darunavir具有明显的抗病毒活性，对多药耐药菌株具有良好的耐药谱和良好的药代动力学特性。2006年6月23日，darunavir被FDA批准为首个治疗耐药HIV的药物。Darunavir是对抗耐药艾滋病毒的新一代抑制剂中的第一种。然而，它远非理想的长期有效治疗。关于口服生物利用度、药片负担和随着时间的推移可能出现的耐药性等问题仍有待解决。基于darunavirv结合HIV蛋白酶的高分辨率x射线晶体结构和许多其他蛋白质配体结构，我们已经设想了许多有趣的设计概念并开发了对抗耐药性的工具。我们已经进行了初步的结构-活性研究，并产生了一些小分子先导物。这项工作现在构成了我们提出的研究的基础，其中包括：(a)基于结构的设计和合成双四氢呋喃衍生的和基于非磺胺的新型药物样pi；(b)设计和开发新的配体和支架，以改善环戊基四氢呋喃（cp-THF）衍生pi的药理学特征；(c)基于结构的新型模板、支架和杂环配体的设计和开发，以生成新型小分子药物样pi；(d)深入耐药研究的表现和选定抑制剂的x射线结构的测定，以获得分子洞察力。本研究整合了有机合成、蛋白质配体x射线晶体学、分子建模以及深入的病毒和细胞生物学研究，以设计下一代HIV-1蛋白酶抑制剂。