Discovery of natural product inhibitors of HIV-1 integrase at Merck

HIV is the causative agent of AIDS, which is currently clinically controlled by drugs that inhibit two of the three enzymes of the virus, namely reverse transcriptase and protease. The development of drugs targeting the third enzyme, integrase, has been elusive. HIV-1 integrase catalyzes the integration of viral DNA into host DNA using three different steps: the assembly of proviral DNA onto integrase, endonucleolytic cleavage of the proviral DNA and strand transfer of the proviral DNA into the host cell DNA. We conducted a screening effort focused on natural product extracts for the discovery of inhibitors of this enzyme and the results are reviewed in this article. The evaluation of over 200,000 extracts originating from more than 50,000 microbial strains equally represented by fungi and actinomycetes led to the discovery of 24 novel classes of chemically diverse natural product inhibitors of HIV-1 integrase, representing a wide variety of classes with molecular weights ranging from 180-1,663 Da and HIV-1 integrase-inhibitory activity IC 5 0 values ranging from 50 nM to > 100 μM. Fungal strains were extremely productive and provided all but two classes of inhibitors. A β-hydroxyketo group was present in many of the compounds identified. If examined carefully, this feature could lead to further development of other compounds if additional 3-dimensional inhibitor-bound enzyme structural information becomes available.