Mutations in the nonstructural protein 3A confer resistance to the novel enterovirus replication inhibitor TTP-8307.
A novel compound, TTP-8307, was identified as a potent inhibitor of the replication of several rhino- and enteroviruses. TTP-8307 inhibits viral RNA synthesis in a dose-dependent manner, without affecting polyprotein synthesis and/or processing. Drug-resistant variants of coxsackievirus B3 were all shown to carry at least one amino acid mutation in the nonstructural protein 3A. In particular, three mutations located in a nonstructured region preceding the hydrophobic domain (V45A, I54F, and H57Y) appeared to contribute to the drug-resistant phenotype. This region has previously been identified as a hot sport for mutations that resulted in resistance to enviroxime, the sole 3A-targeting enterovirus inhibitor reported thus far. This was corroborated by the fact that TTP-8307 and enviroxime proved cross-resistant. It is hypothesized that TTP-8307 and enviroxime disrupt proper interactions of 3A(B) with other viral or cellular proteins that are required for efficient replication.
De Palma
Armando M
AM
Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Thibaut
Hendrik Jan
HJ
van der Linden
Lonneke
L
Lanke
Kjerstin
K
Heggermont
Ward
W
Ireland
Stephen
S
Andrews
Robert
R
Arimilli
Murty
M
Al-Tel
Taleb H
TH
De Clercq
Erik
E
van Kuppeveld
Frank
F
Neyts
Johan
J
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology; D002522:Chlorocebus aethiops; D024882:Drug Resistance, Viral / Q000235:genetics*; D004770:Enterovirus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D029822:Enterovirus B, Human / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006367:HeLa Cells / Q000821:virology; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D009154:Mutation; D010091:Oximes; D017955:Poliovirus / Q000187:drug effects / Q000235:genetics; D012229:Rhinovirus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D013449:Sulfonamides; D014709:Vero Cells / Q000821:virology; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics*; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D001562:Benzimidazoles; D010091:Oximes; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C021595:viroxime