Design and discovery of small molecules inhibiting the interaction of cellular LEDGF/p75 and HIV-1 integrase

Cellular transcription co-activator p75, also known as lens epithelial-derived growth factor (LEDGF/p75), plays an essential role in HIV-1 IN-led integration of viral DNA into the human genome. Designing compounds to disrupt LEDGF/p75-IN complexes serves as a novel mechanistic approach different from current antiviral therapies. The evolution of HIV has afforded the viral species to adapt to external therapeutic pressure and raltegravir-resistant viral strains have been well documented, increasing the need for new IN inhibitors with a different mechanism of action. Mechanistic studies show the majority of reported IN inhibitors effectively chelate with a magnesium ion in the catalytic active site, a region topologically different from the LEDGF/p75 binding site. Thus, key LEDGF/p75 K364 I365 D366 amino acid residues from the IN binding domain laid a foundation for ligand-based pharmacophore models. Herein we report funding from the National Institute of Allergies and Infectious Diseases and the California HIV/AIDS Research Program led to the discovery of more than 100 novel small molecules that successfully inhibited LEDGF/p75-IN complex formation with IC50 values below 50 microM. A small molecule database of 365,000 was searched and compounds that had fitness values above 2.0 were selected for prescreening in an in vitro luminescent proximity assay. Lead inhibitors expanded into training sets using substructure similarity tools and ADMET filters led to the discovery of four novel classes of LEDGF/p75-IN inhibitors and additional potential lead inhibitors. Seven antiviral LEDGF/p75-IN inhibitors were identified from this study.