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HCV eradication with direct acting antivirals (DAAs)? Emilie Estrabaud Service d’Hépatologie et INSERM UMR1149, AP-HP Hôpital Beaujon, Paris, France. [email protected] HCV eradication with direct acting antivirals (DAAs)? HCV replication HCV genome and DAAs targets NS3 inhibitors NS5A inhibitors NS5B inhibitors Take home messages HCV viral cycle Asselah et al. Liver Int. 2015;35 S1:56-64. Direct acting antivirals 5’NTR Structural proteins Nonstructural proteins 3’NTR Metalloprotease Envelope Serine protease Glycoproteins RNA RNA helicase Capsid Cofactors Polymerase C E1 E2 NS1 NS2 NS3 NS4A NS4B NS5A NS5B Protease Inhibitors NS5A Inhibitors Polymerase Inhibitors Telaprevir Daclatasvir Nucs Non-Nucs Boceprevir Ledipasvir Simeprevir ABT-267 Sofosbuvir ABT-333 Faldaprevir GS-5816 VX-135 Deleobuvir Asunaprevir Direct Acting Antivirals: 2015 Asselah et al. Liver Int. 2015;35 S1:56-64. Genetic barrier for HCV direct acting antivirals High 1 mutation= high cost to Nucleos(t)ide fitness, 2-3 additional Analog Inhibitors mutations to increase fitness 2 st generation Protease Inhibitors n Non Nucleos(t)ide Analog Inhibitors : NS5 A Inhibitors 1 st generation Protease 1 mutation= low cost to fitness Inhibitors Low Halfon et al. J Hepatol 2011. Vol 55(1):192-206. HCV protease inhibitors (PI)  Inhibit NS3/NS4A serine protease responsible for the processing of the polyprotein 1st generation 1st generation, 2nd wave 2nd generation Resistance low low high barrier Genotype activity 1: 1 a< 1b All except 3 all Drug drug Important Less Less interaction Drugs Boceprevir Simeprevir (Janssen) MK-5172 Telaprevir Faldaprevir (BI) ACH-2684 Paritaprevir (ABT-450)/r (AbbVie) Vedroprevir (Gilead) Vaniprevir (Merck) Sovaprevir (Achillion) Asunaprevir (BMS) NS3/NS4A structure Repositioning of helicase domain Self cleavage Lipid Bilayer Active Inactive Insertion of the carboxy-terminal tail Bartenschlager et al. Nature Reviews Microbiology 2013 11, 482–496 How inhibitors interact with NS3/NS4A Residues from the catalytic triad: D81 H57 S139 Bartenschlager et al. Nature Reviews Microbiology 2013 11, 482–496 Problem of Cross-Resistance to protease inhibitors NS3/4A V36 T54 V55 Q80 R155 A156 A156 D168 V170 Protease M S A R/K K/T/ S T/V A/E/ A/T Inhibitors Q G/H/ T/Y Telaprevir      Boceprevir        Narlaprevir      Danoprevir   Simeprevir     BI201335    Vaniprevir   Asunaprivir    ABT-450   GS-9451  

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1 mutation= low cost to fitness. 1 mutation= Nature Reviews Microbiology 2013 11, 482–496. Inactive Optimization of NS5A inhibitors structures.
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HCV eradication with direct acting antivirals (DAAs)? Emilie Estrabaud Service d’Hépatologie et INSERM UMR1149, AP-HP Hôpital Beaujon, Paris, France. [email protected] HCV eradication with direct acting antivirals (DAAs)? HCV replication HCV genome and DAAs targets NS3 inhibitors NS5A inhibitors NS5B inhibitors Take home messages HCV viral cycle Asselah et al. Liver Int. 2015;35 S1:56-64. Direct acting antivirals 5’NTR Structural proteins Nonstructural proteins 3’NTR Metalloprotease Envelope Serine protease Glycoproteins RNA RNA helicase Capsid Cofactors Polymerase C E1 E2 NS1 NS2 NS3 NS4A NS4B NS5A NS5B Protease Inhibitors NS5A Inhibitors Polymerase Inhibitors Telaprevir Daclatasvir Nucs Non-Nucs Boceprevir Ledipasvir Simeprevir ABT-267 Sofosbuvir ABT-333 Faldaprevir GS-5816 VX-135 Deleobuvir Asunaprevir Direct Acting Antivirals: 2015 Asselah et al. Liver Int. 2015;35 S1:56-64. Genetic barrier for HCV direct acting antivirals High 1 mutation= high cost to Nucleos(t)ide fitness, 2-3 additional Analog Inhibitors mutations to increase fitness 2 st generation Protease Inhibitors n Non Nucleos(t)ide Analog Inhibitors : NS5 A Inhibitors 1 st generation Protease 1 mutation= low cost to fitness Inhibitors Low Halfon et al. J Hepatol 2011. Vol 55(1):192-206. HCV protease inhibitors (PI)  Inhibit NS3/NS4A serine protease responsible for the processing of the polyprotein 1st generation 1st generation, 2nd wave 2nd generation Resistance low low high barrier Genotype activity 1: 1 a< 1b All except 3 all Drug drug Important Less Less interaction Drugs Boceprevir Simeprevir (Janssen) MK-5172 Telaprevir Faldaprevir (BI) ACH-2684 Paritaprevir (ABT-450)/r (AbbVie) Vedroprevir (Gilead) Vaniprevir (Merck) Sovaprevir (Achillion) Asunaprevir (BMS) NS3/NS4A structure Repositioning of helicase domain Self cleavage Lipid Bilayer Active Inactive Insertion of the carboxy-terminal tail Bartenschlager et al. Nature Reviews Microbiology 2013 11, 482–496 How inhibitors interact with NS3/NS4A Residues from the catalytic triad: D81 H57 S139 Bartenschlager et al. Nature Reviews Microbiology 2013 11, 482–496 Problem of Cross-Resistance to protease inhibitors NS3/4A V36 T54 V55 Q80 R155 A156 A156 D168 V170 Protease M S A R/K K/T/ S T/V A/E/ A/T Inhibitors Q G/H/ T/Y Telaprevir      Boceprevir        Narlaprevir      Danoprevir   Simeprevir     BI201335    Vaniprevir   Asunaprivir    ABT-450   GS-9451  

Description:
1 mutation= low cost to fitness. 1 mutation= Nature Reviews Microbiology 2013 11, 482–496. Inactive Optimization of NS5A inhibitors structures.
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