HIV resistance to clinically approved therapeutics is an increasingly serious clinical problem. Newtherapeutics are needed, especially those against unaddressed HIV targets, such as RT-associatedribonuclease H (RNH). This project will assist in the validation and preclinical development of RNH inhibitors(RNHIs) prepared by semi-synthetic optimization of plant cell culture derived natural products.
The aims ofthis proposed project are 1. to conduct detailed biochemical and virologic characterizations (mechanism ofaction) of a series of novel RNHIs being pursued by scientists at the partnering company, Millenia Hope. Thecurrent leads have sub-micromolar inhibitory activity against RNH in vitro and against HIV replication inPBMC; 2. to screen a library of 150,000 plant-derived partially purified and purified natural products foradditional RNHIs. Hits will be validated in a variety of secondary assays and promising leads will undergooptimizations in other project components; and 3. to characterize in detail the validated hits obtained in thescreening program.The work in this project is an essential component of the overall preclinical development program, and isintimately associated with that of the others (Project 1: Isolation & Optimization, and Project 3: Structural andComputational Biology) in the overall iterative multi-project program. The goal of the entire multi-applicationprogram is to develop 2-3 first generation leads and 4-6 back-up leads with low nM potencies.RNH is essential for HIV replication, yet there are no drugs directed at this target. This research program willdevelop a first-in-class therapeutic agent targeting RNH for use in the treatment of HIV infection. As RNH isa novel target unaddressed by currently used HIV drugs, it is likely that RNHIs developed in this program willbe useful for the treatment of drug-resistant HIV.
