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). Thecentral aims of the proposed work are (i) to determine the structures of HIV-1 RT with a series of novelRNHIs being pursued by scientists at Millenia Hope Inc. as leads on the path to developing a first-in-classtherapeutic agent for the treatment of AIDS; ii) to develop and apply computational methodologies to bothhigh-resolution conformational analysis and refinement of structures determined as well as to assist initerative improvement of lead compounds with favorable antiviral activity that bind to this site; (iii) todetermine 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 mostpromising molecules. The project will involve a close collaboration among the teams of Eddy Arnold andRonald Levy at Rutgers University, Michael Parniak at University of Pittsburgh, and Bahige Baroudy atMillenia Hope Inc.HIV reverse transcriptase (RT) is the target for many clinically important anti-AIDS drugs. Both nucleosideRT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs) are effective for AIDS treatment, but theirefficacy is limited by the emergence of drug-resistant viral variants that affect one or both binding sites. TheRNase H activity of HIV RT is essential for HIV replication. Because the anticipated binding site(s) for theRNHIs under study are expected to be distinct from the NRTI- and NNRTI-binding sites, new RNHIs that willbe developed by the program should have little or no cross-resistance with the existing NRTI and NNRTIfamilies of antivirals, thus providing opportunities for novel therapeutic strategies in the treatment of AIDS.
