TUAA0301 - Oral Abstract Session
Pre-clinical evaluation of HIV replication inhibitors that target the HIV-integrase-LEDGF/p75 interaction
Presented by Frauke Christ (Belgium).
F. Christ1, C. Pickford2, J. Demeulemeester1, S. Shaw2, B.A. Desimmie1, C. Smith-Burchnell2, S. Butler2, M. Westby2, Z. Debyser1
1KULeuven, Laboratory for Molecular Virology and Gene Therapy, Leuven, Belgium, 2Pfizer Inc, Sandwich, United Kingdom
Background: Current HIV-1 integrase inhibitors target the catalytic activity, which is vital for sustained viral infection. Integrase mediates the critical step of proviral DNA integration. Efficient integration also requires a crucial cellular co-factor of HIV-1 integrase, LEDGF/p75, that tethers the viral DNA to the host chromatin. LEDGINs, small molecules designed to bind to the LEDGF/p75 interaction site on IN and to disrupt the interaction, have recently been shown to act as potent inhibitors of HIV replication in cell culture.
Methods: We have now analyzed the detailed mode of action of LEDGINs, dissecting the allosteric nature of inhibition in vitro and analyzing phenotypically their activity in cell culture. Mechanistic studies and combination experiments shed light on potential synergy of LEDGINs with known integration inhibitors. Analysis of the inhibition of a broad spectrum of HIV strains allows predictions on combinations with other drugs such as entry, RT and protease inhibitors.
Results: Biochemical evaluation of LEDGINs demonstrates in addition to a potent inhibition of the integrase-LEDGF/p75 interaction, a block of the catalytic integrase activities. This allosteric inhibition is promoted by the stabilization of the dimer-interface of IN upon LEDGIN binding most likely by affecting interaction with viral DNA. These properties of LEDGINs result in potent inhibition of HIV replication in both MT2 and PBMC cells. Moreover, LEDGINs are active across a broad range of HIV clades. LEDGINs retained full activity against a panel of viruses containing mutations that confer resistance to integrase strand transfer inhibitors. Combining LEDGINs with strand transfer inhibitors demonstrates a synergistic effect of these classes of integration inhibitors.
Conclusions: The biochemical data together with the lack of cross resistance and the observed synergistic effects of LEDGINs in combination with strand transfer inhibitors support the potential for combined use of LEDGINs with strand transfer inhibitors in HIV therapy.
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