HIV RNase H Natural Product Inhibitors Structural and Computational Biology

该项目致力于协助设计和开发核糖核酸酶(RNase)H抑制剂 (RNHIS)使用X射线结晶学(Arnold)和计算建模(Levy)相结合的方法。这个 拟议工作的中心目标是(I)用一系列新颖的方法确定HIV-1RT的结构 千禧希望公司的科学家们正在追求RNHI，将其作为开发一流 用于治疗艾滋病的治疗剂；ii)开发计算方法并将其应用于 对已确定的结构进行高分辨率构象分析和精炼，并协助 迭代改进与该位点结合的具有良好抗病毒活性的先导化合物； 确定HIV-1RT的结构，其具有因程序活性而导致的活性提高的衍生物； 和四)向其他方案组成部分提供结构和计算支助(帕尼亚克和巴鲁迪) 协助解释和设计MOST的生化、生物物理和遗传学研究 前景看好的分子。该项目将涉及Eddy Arnold和Eddy Arnold团队的密切合作 罗杰斯大学的罗纳德·利维，匹兹堡大学的迈克尔·帕尼亚克，以及巴鲁迪的巴鲁迪 千禧希望公司。 HIV逆转录酶是许多临床上重要的抗艾滋病药物的靶标。两种核苷 逆转录酶抑制剂(NRTI)和非核苷类逆转录酶抑制剂(NNRTI)对艾滋病治疗有效，但其 影响一个或两个结合位点的抗药性病毒变种的出现限制了疗效。这个 HIV RT的RNaseH活性是HIV复制所必需的。因为预期的结合位点(S) 预计正在研究的RNHI将不同于NRTI和NNRTI结合位点，这两种新的RNHI将 由程序开发的应与现有的NRTI和NNRTI有很小或没有交叉耐药性 抗病毒药物家庭，从而为艾滋病的治疗提供了新的治疗策略。

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.