BBI-Biotech Research Laboratories and the University of North Carolina are collaborating in a novel approach to identify natural product derivatives that block HIV infection, by focusing on specific plant families with a history of application in traditional medicine. This project proposal will characterize the six most potent drug candidates discovered in the collaboration: A) Three related coumarins: Di-Camphanoyl-Khallactone (DCK), 4-methyl DCK and thiolactone DCK; B) Three related triterpenes: Dimethylsuccinylbetulinic acid (DSB), Dimethylsuccinyldihydrobetulinic acid (DSD) and Dimethylglutarylbetulin (DGB). These compounds inhibit HIV replication at nanomolar concentrations, with therapeutic indices in vitro of greater than 10,000. The goal of this proposal is to identify the most suitable compound for future clinical development. The compounds will be compared for their breadth of inhibitory activity in vitro against a panel of primary HIV- 1 isolates. A detailed investigation of mechanisms of action will also be performed. A rat model will then be used to analyze the compounds in vivo for oral bioavailability, plasma pharmacokinetics and toxicity. Following the identification of a suitable lead compound, it will be tested in pre-clinical safety and in vivo efficacy studies during the Phase II grant period, the objective being to initiate clinical trials by the end of Phase II. PROPOSED COMMERCIAL APPLICATIONS: The goal is to identify a natural product-derived drug for HIV infection, with advantages over drugs that are currently approved or in development. Emphasis will be placed on a drug suitable for use in combination therapy regimens, specifically one which acts at a different stage in the viral life cycle than approved drugs and exhibits minimal toxicity.