Extended interaction networks with HCV protease NS3-4A substrates explain the lack of adaptive capability against protease inhibitors.
Adaptor Proteins, Signal Transducing
/ chemistry
Amino Acid Substitution
Cell Line, Tumor
Hepacivirus
/ physiology
Humans
Molecular Dynamics Simulation
Mutation, Missense
Protease Inhibitors
/ pharmacology
Serine Proteases
/ chemistry
Viral Nonstructural Proteins
/ antagonists & inhibitors
Virus Replication
/ drug effects
adaptation
drug resistance
evolution
hepatitis C virus (HCV)
mitochondrial antiviral signaling protein (MAVS)
molecular adaptation
molecular biology
molecular dynamics
protease inhibitor
replicative fitness
resistance mutation
serine protease (NS3-4A)
structure constraints
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
02 10 2020
02 10 2020
Historique:
received:
16
04
2020
revised:
26
07
2020
pubmed:
5
8
2020
medline:
4
2
2021
entrez:
5
8
2020
Statut:
ppublish
Résumé
Inhibitors against the NS3-4A protease of hepatitis C virus (HCV) have proven to be useful drugs in the treatment of HCV infection. Although variants have been identified with mutations that confer resistance to these inhibitors, the mutations do not restore replicative fitness and no secondary mutations that rescue fitness have been found. To gain insight into the molecular mechanisms underlying the lack of fitness compensation, we screened known resistance mutations in infectious HCV cell culture with different genomic backgrounds. We observed that the Q41R mutation of NS3-4A efficiently rescues the replicative fitness in cell culture for virus variants containing mutations at NS3-Asp
Identifiants
pubmed: 32747444
pii: S0021-9258(17)49834-6
doi: 10.1074/jbc.RA120.013898
pmc: PMC7535904
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
MAVS protein, human
0
Protease Inhibitors
0
Viral Nonstructural Proteins
0
NS3-4A serine protease, Hepatitis C virus
EC 3.4.-
Serine Proteases
EC 3.4.-
Banques de données
PDB
['2OC8', '3RC5', '1ACB']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
13862-13874Subventions
Organisme : NIAID NIH HHS
ID : R01 AI110358
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI146227
Pays : United States
Informations de copyright
© 2020 Dultz et al.
Déclaration de conflit d'intérêts
Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article.
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