On the cell biology of HIV integration from basic research to development of novel antiviral drugs.

Viruses in general, HIV in particular, use cellular proteins or cofactors to achieve their replication cycle. Our recent research efforts resulted in the identification and validation of two new cellular cofactors of HIV replication: LEDGF/p75 and transportin-SR2. LEDGF/p75 is a cellular transcriptional coactivator used by the virus to tether the preintegration complex onto the chromosome; transportin-SR2 is a cellular import factor used by the virus for nuclear import into the nucleus. After validation of LEDGF/p75 as an antiviral target, we initiated a drug discovery program to develop small molecule inhibitors of integrase-LEDGF/p75 interaction. Using molecular modeling, medicinal chemistry, crystallography and virology, our team developed LEDGINs, the first-in-class small molecule inhibitors of HIV targeting integrase/LEDGF/p75 interaction. As for transportin-SR2, this protein was identified by yeast-two-hybrid screening and validated as a nuclear import factor for HIV. A drug discovery program for inhibitors of nuclear import is ongoing. Together our research results provide a paradigm shift in antiviral research. Yes, small molecules can be developed inhibiting the protein-protein interaction between a viral protein and a cellular cofactor. In a broader perspective our research strongly supports the development of protein-protein interaction inhibitors as drugs.