Novel anti AIDS lead compounds that inhibit the viral integrase protein

The HIV-1 Integrase protein (IN) mediates the integration of the viral cDNA into the host genome. IN is an emerging target for the design of novel drugs against AIDS, and the fi rst IN-inhibitor, Raltegavir, was approved by the FDA in October 2007. Our research in the past few years focuses on the development of peptide inhibitors of IN. We designed inhibitors using two approaches: (1) Rational design based on protein-protein interactions of IN: Peptidic sequences derived from IN-binding sites of IN-binding proteins are already optimized by nature to bind IN and have the potential to inhibit it. Using this approach we developed several IN inhibitors: two peptides derived from the IN-binding loops of the cellular binding partner of IN, LEDGF/p75 (LEDGF 361-370 and LEDGF 401-412), and two peptides derived from the HIV-1 Rev protein, which we found to bind IN; (2) A peptide selected using combinatorial library screening using the yeast-2-hybrid system, revealed a 20-mer peptide, termed by us IN(1) All fi ve peptides bound IN with low micromolar affi nity and inhibited the DNA-binding of IN as well as its enzymatic activity in vitro. These peptides penetrated cells and consequently blocked HIV-1 replication in infected cultured cells due to the lack of integration. The most potent peptides in vitro and in cells were LEDGF 361-370 and Rev 13-23. These two peptides signifi cantly inhibited HIV-1 infection in mice model. We conclude that the five peptides, particularly LEDGF 361-370 and Rev 13-23, are promising anti-HIV lead compounds.