AIDS2012 TUAA0301 Pre-clinical Evaluation of HIV Replication Inhibitors that Target the HIV Integrase- LEDGF/p75 Interaction Frauke Christ , Chris Pickford, Jonas Demeulemeester, Stephen Shaw, Belete Desiemmie, Caroline Smith- Burchnell, Scott Butler, Mike Westby, Zeger Debyser Molecular Virology and Gene Therapy KU Leuven Belgium
AIDS2012 TUAA0301. Pre-clinical Evaluation of HIV Replication Inhibitors that Target the HIV Integrase -LEDGF/p75 Interaction Frauke Christ , Chris Pickford, Jonas Demeulemeester, Stephen Shaw, Belete Desiemmie, Caroline Smith-Burchnell, Scott Butler, Mike Westby, Zeger Debyser - PowerPoint PPT Presentation
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AIDS2012 TUAA0301
Pre-clinical Evaluation of HIV Replication Inhibitors that Target the HIV Integrase-
LEDGF/p75 Interaction
Frauke Christ, Chris Pickford, Jonas Demeulemeester, Stephen Shaw, Belete Desiemmie, Caroline Smith-Burchnell, Scott Butler, Mike Westby, Zeger Debyser
Molecular Virology and Gene TherapyKU Leuven
Belgium
LEDGF/p75 is a co-factor of HIV integrase (Cherepanov et al, JBC, 2003) that tethers the provirus to the cellular genome.
The interface of LEDGF/p75 and integrase is well defined (Cherepanov et al. PNAS, 2005)
Overexpression of the LEDGF/p75 integrase binding domain (IBD) inhibits HIV replication (De Rijck et al., JVI, 2006)
LEDGINs, first in class allosteric integration inhibitors bind to the LEDGF/p75 binding site on integrase. (Christ, et al., Nat. Chem. Biol. 2010)
LEDGF/p75 is a novel target for antiviral therapy
LEDGINs, first-in-class antivirals 1.84 Å co-crystal structure
LEDGINs are a novel class of HIV-replication inhibitors designed on the basis of a pharmacophore model.
By combination of medicinal chemistry and structural biology different series of compounds have been developed with activities in the low nanomolar range and selectivity >5000.
LEDGINs block the LEDGF/p75-IN interaction and bind to an allosteric site on integrase.
LEDGINs are active against a wide range of INSTI resistant mutants. LEDGINs are active against a broad range of HIV-1 subtypes.
CX05045raltegravir
LEDGIN raltegravir capsid inhibitor
(Christ, et al., AAC, 2012)
LEDGINs activity against resistance mutants
LEDGIN resistance mutants were identified in serial passaging experiments with HIV-1 (NL4-3)
Mutations were introduced to the IN gene of NL4-3 by site directed mutagenesis
Series 2 and Series 3 are significantly less susceptible to resistance mutations of series 1
None of the LEDGINs lose activity in the presence of STI resistance mutations
Combination of LEDGINs and INSTIs
LEDGINs and raltegravir act additive with a tendency towards synergy when combined for therapy.
(Christ, et al., AAC, 2012)
LEDGINs impair the infectivity of viral particles
Alike for raltegravir mature viral particles are produced in the presence of LEDGINs but the viral particles produced in presence of CX05045 are impaired in their
infectivity LEDGINs do not only inhibit the provirus formation but alo the infectivity of newly
produced viral particles.
Production of IIIB Infectivity of IIIB
DMSO raltegravir ritonavir CX05045
(Christ, et al., AAC, 2012)
DMSO raltegravir ritonavir CX05045
Summary
LEDGINs are a novel promising class of inhibitors potently blocking HIV replication.
LEDGINs have multimodal mechanism direct inhibition of the LEDGF/p75-IN interaction
allosteric inhibition of the catalytic activity of integrase
Viral particles produced in the presence of LEDGINs are severly impaired for their infectivity.
LEDGINs act at the same step of HIV replication like INSTIs and potently block INSTI resistant strains.
Due to a lack of cross-resistance and additive effects of LEDGINs and raltegravir in combination experiments LEDGINs hold great promise for further clinical development.
Thank you….
KU LeuvenMolecular Medicine: Belete A. Desimmie, Jonas Demeulemeester, Barbara Van Remoortel, Nam Joo Van der Veken, Zeger Debyser