Mutations in the nonstructural protein 3A confer resistance to the novel enterovirus replication inhibitor TTP-8307.
SourceAntimicrobial Agents and Chemotherapy, 53, 5, (2009), pp. 1850-7
Article / Letter to editor
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Antimicrobial Agents and Chemotherapy
SubjectN4i 1: Pathogenesis and modulation of inflammation; NCMLS 1: Infection and autoimmunity
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.
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