| Title | Mutations in the nonstructural protein 3A confer resistance to the novel enterovirus replication inhibitor TTP-8307. | ||
| Author | De Palma, Armando M; Thibaut, Hendrik Jan; van der Linden, Lonneke; Lanke, Kjerstin; Heggermont, Ward; Ireland, Stephen; Andrews, Robert; Arimilli, Murty; Al-Tel, Taleb H; De Clercq, Erik; van Kuppeveld, Frank; Neyts, Johan | ||
| Journal | Antimicrob Agents Chemother | Publication Year/Month | 2009-May |
| PMID | 19237651 | PMCID | PMC2681499 |
| Affiliation | 1.Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium. | ||
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.