title: Mutations in the nonstructural protein 3A confer resistance to the novel enterovirus replication inhibitor TTP-8307.
abstract: 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.
authors.affiliation: Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Armando M
authors.initials: AM
authors.lastname: De Palma
authors.forename: Hendrik Jan
authors.initials: HJ
authors.lastname: Thibaut
authors.forename: Lonneke
authors.initials: L
authors.lastname: van der Linden
authors.forename: Kjerstin
authors.initials: K
authors.lastname: Lanke
authors.forename: Ward
authors.initials: W
authors.lastname: Heggermont
authors.forename: Stephen
authors.initials: S
authors.lastname: Ireland
authors.forename: Robert
authors.initials: R
authors.lastname: Andrews
authors.forename: Murty
authors.initials: M
authors.lastname: Arimilli
authors.forename: Taleb H
authors.initials: TH
authors.lastname: Al-Tel
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Frank
authors.initials: F
authors.lastname: van Kuppeveld
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
mesh_terms: 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*
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D010091:Oximes; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C021595:viroxime