Pre-clinical evaluation of HIV replication inhibitors that target the hiv integrase-LEDGF/p75 interaction

PRE-CLINICAL EVALUATION OF HIV REPLICATION INHIBITORS THAT TARGET THE HIV INTEGRASE-LEDGF/P75 INTERACTION Chris Pickford (1), Frauke Christ (2), Stephen Shaw (1), Kevin Whitby (1), Belete A. Desimmie (2), Caroline Smith-Burchnell (1), Scott Butler (1), Arnaud Marchand (2), Patrick Chaltin (2), Zeger Debyser (2), Mike Westby (1) (1) Infectious Diseases Group, Pfizer Ltd, Sandwich, Kent, UK; (2) Molecular & Cellular Medicine, Katholieke Universiteit Leuven, Leuven, Belgium Current HIV-1 integrase inhibitors target the catalytic activity of the viral enzyme HIV-1 integrase, which is critical for the HIV-1 replication process and sustained viral infection. The viral enzyme mediates the critical step of pro-viral DNA integration within the host cell genome via a two step process of 3’-processing followed by strand transfer. A crucial cellular co-factor for HIV-1 integrase catalysed strand transfer is lens epithelium-derived growth factor (LEDGF) (Cherepanov et al, 2003). It has recently been demonstrated that small molecules designed to disrupt the interaction between HIV integrase and LEDGF/p75 are potent inhibitors of HIV replication in cell culture (Christ et al, 2010). Further biochemical evaluation of these compounds demonstrates that in addition to potently blocking the interaction between integrase and LEDGF, they also block integrase strand transfer and 3’ processing activity. These properties of integrase-LEDGF/p75 interaction inhibitors result in potent inhibition of HIV replication in both MT2 and PBMC cells. Furthermore, integrase-LEDGF/p75 interaction inhibitors are active across a broad range of HIV clades. In vitro resistance studies have demonstrated that the main pathway to resistance for integrase-LEDGF/p75 interaction inhibitors is through a A128T mutation in integrase. Cross resistance analysis has demonstrated that raltegravir, a launched integrase strand transfer inhibitor, is active against viruses containing the resistance mutations arising in response to integrase-LEDGF/p75 interaction inhibitors. Furthermore, a panel of viruses containing mutations that confer resistance to integrase strand transfer inhibitors did not have a reduced susceptibility to the integrase-LEDGF/p75 interaction inhibitors. Combining integrase-LEDGF/p75 interaction inhibitors with strand transfer inhibitors in antiviral assays demonstrated that there is an additive effect of these compound classes. The cross resistance data together with the additive effects support the support the potential for combined use of integrase-LEDGF/p75 interaction inhibitors with strand transfer inhibitors in HIV-infected patients. P. Cherepanov, G. Maertens, P. Proost, B. Devreese, J. Van Beeumen, Y. Engelborghs, E. De Clercq, and Z. Debyser. 2003. HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. J. Biol. Chem. 278: 372-381. F. Christ, A. Voet, A. Marchand, S. Nicolet, B. A. Desimmie, D. Marchand, D. Bardiot, N. J. Van der Veken, B. Van Remoortel, S. V. Strelkov, M. De Maeyer, P. Chaltin, Z. Debyser. 2010. Rational design of small –molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nat. Chem. Biol. 6: 442-448.status: publishe