HIV RNase H Natural Product Inhibitors Structural and Computational Biology

该项目专注于利用x射线晶体学（Arnold）和计算建模（Levy）的结合，协助设计和开发核糖核酸酶（RNase） H抑制剂（RNHIs）。拟议工作的中心目标是(i)确定HIV-1 RT的结构，由Millenia Hope Inc.的科学家正在研究一系列新颖的RNHIs，作为开发治疗艾滋病的一流治疗剂的先导；Ii)开发和应用计算方法进行高分辨率构象分析和确定的结构的改进，并协助迭代改进结合该位点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，并通过程序活性提高衍生物的活性；iv)为其他项目组件（Parniak和Baroudy）提供结构和计算支持，以协助最有希望的分子的生化，生物物理和遗传研究的解释和设计。该项目将涉及艾迪·阿诺德和

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.