HIV RNase H Natural Product Inhibitors Structural and Computational Biology

该项目专注于利用X射线结晶学(Arnold)和计算模拟(Levy)相结合的方法来协助设计和开发核糖核酸酶(RNase)H抑制剂(RNHI)。拟议工作的中心目标是(I)利用Millenia Hope Inc.的科学家正在追求的一系列新型RNHI确定HIV-1 RT的结构，作为开发用于治疗艾滋病的一流治疗剂的道路上的领先；ii)开发和应用计算方法来进行高分辨率构象分析和所确定的结构的精炼，以及帮助迭代改进与该部位结合的具有良好抗病毒活性的先导化合物；(Iii)确定HIV-1 RT的结构，其衍生物的活性因程序活性而提高；以及iv)为其他计划组成部分(Parniak和Baroudy)提供结构和计算支持，以协助解释和设计最有希望的分子的生化、生物物理和遗传学研究。该项目将涉及Eddy Arnold和Eddy Arnold团队的密切合作 罗格斯大学的罗纳德·利维，匹兹堡大学的迈克尔·帕尼亚克，以及千禧希望公司的巴鲁迪。 HIV逆转录酶是许多临床上重要的抗艾滋病药物的靶标。核苷类逆转录酶抑制剂(NRTI)和非核苷类逆转录酶抑制剂(NNRTI)对艾滋病的治疗都是有效的，但由于出现了影响一个或两个结合位点的耐药病毒变异体，其疗效受到限制。HIV RT的RNaseH活性是HIV复制所必需的。由于正在研究的RNHI的预期结合位点(S)预计与NRTI和NNRTI结合位点不同，该计划将开发的新RNHI应该与现有的NRTI和NNRTI家族的抗病毒药物几乎没有交叉耐药性，从而为艾滋病治疗的新治疗策略提供机会。

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.