Our objective is to identify and optimize plant derived small molecules for the inhibition of HIV RT-associatedRNase H (RNH) avtivity, a novel target for HIV intervention. The overall goal of this poject is to recommend2-3 compounds for development (CD) from the initial screen of 10,000 fractions (1st program) andrecommend 4-6 CDs (back up program) from screening the rest of the plant derived library (150,000fractions). The first generation CDs should attain an IC50 of 50 nm or better while second generation CDsshould have single digit nm IC50. These compounds should be effective in ihibiting HIV strains that areresistant to current drugs. RNH inhibitors (RNHI) will be optimized using biochemical and virologic datainitially followed by utilizing computanional and structural information obtained from X-ray crystallographicstudies of RT-RNHI complexes (see other projects within this RFA) to allow rational design of analogs thatwill be either synthesized or semi-synthesized. In case a semi-synthetic approach is adopted, we can useour 50 L bioreactor to produce gram quantities of the starting material to allow us to generate a small libraryof analogs. In addition, combinatorial and parallel synthesis will be utilized for some molecules to increaseboth the quantity and chemical diversity of potential leads. We will adhere to established guidlines such asthe Lipinski 'Rule of five' to increase our chances of obtaining drug like molecules. Analogs that showimproved acivity will be subjected to ADME/PK studies in order to select for drug like leads. This process willbe repeated until we achieve the profile of a CD described in Table 4. We would like to include yet anotherapproach in our drug discovery of RNHI. We will exploit the generation of metabolites of some of our leadsas a source of new chemotypes for identifyiing RNHI. We are very encouraged by the results that weobtained so far (Tablel). There is a strong correlation between the biochemical and cell-based values, somehaving an IC50<1uM with an excellent therapeutic Index >200. This represents a major step forward inidentifying and developing RNHIs. It is a tribute to the plant cell culture technology that we developed so far.A highly diverse library that originated from more than 2200 plant species, representing 284 plant families,that is charecarized by a high reproducibility of secondary metabolite production. This project has enormouspotential impact in delivering a new class of HIV drugs.
