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: 8218096
• 负责人: EDWARD ARNOLD
• 金额: $ 42.67万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8218096
• 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; 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; 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; structural biology; 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.

该项目集中于使用X射线晶体学（Arnold）和计算建模（Levy）的组合来辅助核糖核酸酶（RNase）H抑制剂（RNHIs）的设计和开发。拟议工作的中心目标是（i）确定HIV-1 RT的结构，其中一系列新的RNHI正由Millenia Hope Inc.的科学家进行研究。作为开发用于治疗艾滋病的一流治疗剂的途径上的先导; ii）开发并应用计算方法学来进行高分辨率构象分析和确定结构的细化，以及帮助迭代改进具有与该位点结合的有利抗病毒活性的先导化合物;（iii）确定具有由程序活性产生的改进活性的衍生物的HIV-1 RT的结构;以及iv）为其他程序组件提供结构和计算支持（Parniak和Baroudy），以协助解释和设计最有前途的分子的生物化学，生物物理学和遗传学研究。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亚克和千禧希望公司的巴希格巴鲁迪。 HIV逆转录酶（RT）是许多临床上重要的抗艾滋病药物的靶点。核苷类逆转录酶抑制剂（NRTI）和非核苷类逆转录酶抑制剂（NNRTI）都对艾滋病治疗有效，但它们的疗效受到影响一个或两个结合位点的耐药病毒变异体的出现的限制。HIV RT的RNase H活性对HIV复制至关重要。由于所研究的RNHI的预期结合位点与NRTI和NNRTI结合位点不同，因此该计划将开发的新RNHI与现有的NRTI和NNRTI抗病毒药物家族几乎没有交叉耐药性，从而为治疗艾滋病的新治疗策略提供了机会。