Thinc meeting location:Prague, Czech Republic date:29-30 January 2009
An essential step during the HIV life cycle is the integration of the viral cDNA into the human genome. HIV-1 integrase mediates integration in a tight complex with the cellular cofactor: LEDGF/p75. Disruption of the interaction interferes with HIV replication and therefore provides an interesting new drug target for antiretroviral therapy. Here we present the structure based discovery work flow for a series of small molecule inhibitors that bind to HIV-1 integrase and block the interaction with LEDGF/p75. The work flow was set up according to a funnel principle based on 2D filtering (selecting for protein-protein interaction inhibitors), interface base pharmacophores, docking and validation of the binding modes). The activity and selectivity of the molecules were confirmed in Alphascreen based assays, that measure protein-protein interaction in vitro, and furthermore by crystallography. The hits present a new class of inhibitors with potential for future development for antiretroviral therapy.