HCV eradication with direct acting antivirals (DAAs)?

23 Pages·2015·2.65 MB·English

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  