These investigators are continually pursuing their long-term screening of medicinal plant extracts and subsequent structural modification of discovered leads. The goal of the proposed research is to discover novel anti-HIV compounds from plant-derived natural products and their analogs. Specifically, they plan to isolate and identify the potent anti-HIV principles from extracts of 71 previously unexplored plant species using bioassay-directed isolation and structural chacterization. Initially, inhibition of HIV replication is measured using an in vitro P24 antigen capture assay in H9 lymphocytes. The structures of isolated anti-HIV principles will be determined using modern spectral and x-ray analyses. Promising, new active leads will be selected for structural modification and synthesis of analogs on new active leads in order to determine structure-activity relationships as well as to improve their pharmacological profiles. Mechanisms of action will be investigated using biochemical and cell culture-based assays. These leads should provide new, effective, and less toxic drug candidates, which may circumvent drug resistance, target different stages in the viral life cycle, exhibit minimal toxicity, and have lower manufacturing costs. Two compounds, 4-methy DCK and DSB, have attractive properties for further development, based on novel mechanisms of action compared to approved HIV drugs; high in vitro potency against primary HIV-1 isolates; high in vitro therapeutic indices; and ease of synthesis. Studies of the compound's in vivo properties (pK, bioavailability and toxicity) are continuing, as are mechanism of action studies. Additional studies planned include in vitro analyses of the drug candidates' synergy or antagonism when used in combination with approved HIV drugs. In vitro studies of the rate of HIV resistance development will also be performed. The applicant hopes that at least one of these two structurally diverse compounds, or one of their analogs, should exhibit suitable properties for moving forward into preclinical toxicology testing and scale-up manufacturing during 2000, with the goal of submitting an IND by 2001.
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