HIV RNase H Natural Product Inhibitors Structural and Computational Biology

HIV RNase H 天然产物抑制剂结构与计算生物学

• 批准号: 8043512
• 负责人: EDWARD ARNOLD
• 金额: $ 43.48万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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/8043512
• 关键词: Achievement; Acquired Immunodeficiency Syndrome; Affect; Algorithms; Anti-HIV Agents; Antiviral Agents; Binding; Binding Sites; Biochemical; Biological Factors; Clinical; Collaborations; Complex; Computational Biology; Computer Simulation; Computer software; Computing Methodologies; Crystallization; Data; Data Collection; Development; Docking; Drug Kinetics; Elements; Family; Foundations; Free Energy; Genetic; Goals; Grant; HIV; HIV-1 Reverse Transcriptase; Laboratories; Lead; Libraries; Ligand Binding; Ligands; Methods; Modeling; Molecular Conformation; Nucleic Acids; Nucleosides; Phase; Photons; Physiological; Phytochemical; Preclinical Testing; Protein Binding; Proteins; RNA; RNA-Directed DNA Polymerase; Resistance; Resolution; Reverse Transcriptase Inhibitors; Ribonuclease H; Ribonucleases; Roentgen Rays; Sampling; Scientist; Scoring Method; Screening procedure; Series; Side; Site; Source; Structural Models; Structure; Synchrotrons; Techniques; Therapeutic Agents; Universities; Update; Variant; Vertebral column; Work; X-Ray Crystallography; analog; base; design; driving force; drug resistant virus; experience; improved; inhibitor/antagonist; model development; non-nucleoside reverse transcriptase inhibitors; novel; novel therapeutics; programs; reconstruction; resistant strain; restraint; therapeutic target; three dimensional structure; tool

This project concentrates on assisting the design and development of ribonuclease (RNase) H inhibitors (RNHIs) using a combination of X-ray crystallography (Arnold) and computational modeling (Levy). The central aims of the proposed work are (i) to determine the structures of HIV-1 RT with a series of novel RNHIs being pursued by scientists at Millenia Hope Inc. as leads on the path to developing a first-in-class therapeutic agent for the treatment of AIDS; ii) to develop and apply computational methodologies to both high-resolution conformational analysis and refinement of structures determined as well as to assist in iterative improvement of lead compounds with favorable antiviral activity that bind to this site; (iii) to determine the structures of HIV-1 RT with derivatives with improved activity that result from program activity; and iv) to provide structural and computational support to other program components (Parniak and Baroudy) to assist in the interpretation and design of biochemical, biophysical, and genetic studies of the most promising molecules. The project will involve a close collaboration among the teams of Eddy Arnold and Ronald Levy at Rutgers University, Michael Parniak at University of Pittsburgh, and Bahige Baroudy at Millenia Hope Inc. HIV reverse transcriptase (RT) is the target for many clinically important anti-AIDS drugs. Both nucleoside RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs) are effective for AIDS treatment, but their efficacy is limited by the emergence of drug-resistant viral variants that affect one or both binding sites. The RNase H activity of HIV RT is essential for HIV replication. Because the anticipated binding site(s) for the RNHIs under study are expected to be distinct from the NRTI- and NNRTI-binding sites, new RNHIs that will be developed by the program should have little or no cross-resistance with the existing NRTI and NNRTI families of antivirals, thus providing opportunities for novel therapeutic strategies in the treatment of AIDS.

本计画致力于协助核糖核酸酶H抑制剂的设计与开发 使用X射线晶体学（Arnold）和计算建模（Levy）的组合的RNHIs。的 所提出的工作的中心目标是（i）确定HIV-1 RT的结构， Millenia Hope Inc.的科学家正在研究RNHI。作为开发一流的 用于治疗艾滋病的治疗剂; ii）开发和应用计算方法， 高分辨率构象分析和确定的结构的细化，以及协助 迭代改进结合该位点的具有有利抗病毒活性的先导化合物;（iii） 确定HIV-1 RT的结构，其衍生物具有由程序活动产生的改进的活性; 和iv）为其他程序组件（Parniak和Baroudy）提供结构和计算支持 协助解释和设计生物化学，生物物理学和遗传学研究， 有前途的分子该项目将涉及埃迪阿诺德和 罗格斯大学的罗纳德利维、匹兹堡大学的迈克尔帕尼克和 美年希望公司 HIV逆转录酶（RT）是许多临床上重要的抗艾滋病药物的靶点。双核苷 RT抑制剂（NRTI）和非核苷RT抑制剂（NNRTI）对于AIDS治疗是有效的，但是它们的 影响一个或两个结合位点的抗药性病毒变体的出现限制了效力。的 HIV RT的RNase H活性对HIV复制至关重要。因为预期的结合位点 研究中的RNHI预期不同于NRTI和NNRTI结合位点，新的RNHI将 由该计划开发的药物应与现有的NRTI和NNRTI很少或没有交叉耐药性 抗病毒药物家族，从而为治疗艾滋病的新治疗策略提供了机会。