The major objective of Associate Project-3 (AP-3) is to isolate and identify specific inhibitors of HIV replication and agents active against chloroquine-resistant Plasmodium falciparum. It will provide bioassay support for the discovery of natural products effective against malaria and AIDS through the screening of approximately 500 plant extracts annually followed by bioactivity fractionation procedures. Source materials for evaluation will be selected and collected under and Lao People's Democratic Republic. A primarily biodiversity-based selection approach will be adopted, although ethnobotanical inquiry may be employed to a limited extent. This project will also perform initial extraction of plant materials and scale-up isolation of confirmed active phytochemicals. Spectroscopic and chemical methods will be used to determine the structures of pure bioactive compounds. Efforts will be made to minimize the re-isolation of compounds with known anti-HIV or anti-malarial properties through literature (NAPRALERT) and LC/MS/MS dereplication techniques. Additionally, several inhibitors of HIV-1 reverse transcriptase (RT) and numerous promising anti-malarial compounds and extracts have been identified through ongoing collaborative drug discovery efforts with researchers in Vietnam. These biologically active natural products will be re-isolated and evaluated in more physiologically complex bioassay systems and relevant mechanistic assays in order to prioritize them for more advanced in vivo studies. In concert with Glaxo Wellcome, active compounds will be evaluated as candidates for development as drugs. Alternatively, novel isolates may be considered as new leads for the development of selective inhibitors.
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