L15/16 HepC (3) Flashcards
What is combination chemotherapy of IFN based regimes for HCV treatment?
IFN-a : activates IFN mediated antiviral responses
Pegylated IFN - Albuferon used (conjugated to albumin)
Ribavirin
What are the problems based with HCV treatment?
Response varies with genotype
non-responders
relapse after therapy
side effects - reduction in neutrophil levels, anaemia (ribavirin)
costly
What are DAAs?
drug-like molecule that interferes with function of viral protein by binding DIRECTLY TO IT
Common interaction sites of DAAs?
bind active site - mimic substrate (competitive)
block entry to active site
bind to protein to prevent proper folding (allosteric)
How are replicons used for drug development?
screen large compound libraries with luciferase based subgenomic replicon
identify DAAs - compounds that block replicon replication
What are the 3 common targets of DAAs in HCV?
NS3
NS5A
NS5B
How does resistance arise in HCV patients treated with a SINGLE DAA?
mutations in NS3 sequences in a few days
How does resistance develop in HCV patients?
DAA treatment provides selection pressure
QUASI SPECIES
randomly occurring mutants are resistant
What is the genetic barrier to resistance?
Substitutions that prevent DAA binding usually reduce protein function - reducing virus replicative fitness
What can raise the genetic barrier to DAA resistance?
if substitutions are needed are multiple sites to overcome drug effects
avoid cross resistance
produce compounds with high potency - resistance does not overcome antiviral effect
What are the NS3 protease inhibitors?
TELAPREVIR
BOCEPREVIR
SIMEPREVIR
VOXILAPREVIR
1st generation NS3 inhibitors?
TELAPREVIR
BOCEPREVIR
2nd generation NS3 inhibitors?
SIMEPREVIR
3rd generation NS3 inhibitors?
VOXILAPREVIR
What are the NS5A inhibitors?
LEDIPASVIR
DACLATASVIR
VELPATASVIR
