Mining the extensive chemical diversity of the NCI natural products repository for new agents that can target HIV

Extracts from a wide variety of terrestrial plants, marine organisms, and microbial isolates have been screened for anti-HIV properties using a cell-based, infectious virus assay format. This type of phenotypic screening can identify inhibitory samples that target virtually any step in the virus infection or replication process. Assay-guided fractionation of active extracts has provided an array of novel, HIV inhibitory compounds that span many different structural classes. These discoveries include new small molecule inhibitors such as alkaloids, terpenoids, quinones, and coumarins, as well as some larger anti-HIV peptides. Biological characterization of lead compounds revealed these metabolites can impact critical processes such as virus entry into host cells, membrane integrity, or reverse transcription of viral RNA. Several of these agents have undergone extensive preclinical evaluations and one has advanced to a Phase II clinical study. The combination of a large, diverse library of natural product samples and a new antiviral screening platform has provided a valuable resource for discovery of novel HIV inhibitors.