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AG110 is a highly selective inhibitor of pestivirus replication, with an EC50 of 1.2 µM against bovine viral diarrhea virus, targeting the viral RNA-dependent RNA polymerase.
AG110 is a potent and selective inhibitor of pestivirus replication that targets the viral RNA-dependent RNA polymerase.
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AG110 advances pestivirus RdRp inhibition in preclinical models; leaves open translation to in vivo efficacy and veterinary use.
Ethyl 2-methylimidazo[1,2-a]pyrrolo[2,3-c]pyridin-8-carboxylate (AG110) was identified as a potent inhibitor of pestivirus replication. The 50% effective concentration values for inhibition of bovine viral diarrhea virus (BVDV)-induced cytopathic effect, viral RNA synthesis, and production of infectious virus were 1.2 +/- 0.5 microM, 5 +/- 1 microM, and 2.3 +/- 0.3 microM, respectively. AG110 proved inactive against the hepatitis C virus and a flavivirus. AG110 inhibits BVDV replication at a time point that coincides with the onset of intracellular viral RNA synthesis. Drug-resistant mutants carry the E291G mutation in the viral RNA-dependent RNA polymerase (RdRp). AG110-resistant virus is cross-resistant to the cyclic urea compound 1453 which also selects for the E291G drug resistance mutation. Moreover, BVDV that carries the F224S mutation (because of resistance to the imidazopyridine 5-[(4-bromophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine [BPIP]and VP32947) is also resistant to AG110. AG110 did not inhibit the in vitro activity of recombinant BVDV RdRp but inhibited the activity of BVDV replication complexes (RCs). Molecular modeling revealed that E291 is located in a small cavity near the tip of the finger domain of the RdRp about 7 A away from F224. Docking of AG110 in the crystal structure of the BVDV RdRp revealed several potential contacts including with Y257. The E291G mutation might enable the free rotation of Y257, which might in turn destabilize the backbone of the loop formed by residues 223 to 226, rendering more mobility to F224 and, hence, reducing the affinity for BPIP and VP32947. It is concluded that a single drug-binding pocket exists within the finger domain region of the BVDV RdRp that consists of two separate but potentially overlapping binding sites rather than two distinct drug-binding pockets.
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Paeshuyse et al. (2007) studied Pestivirus infection (Bovine viral diarrhea virus). AG110 vs. Untreated control was evaluated on 50% effective concentration (EC50) for inhibition of BVDV-induced cytopathic effect (EC50 1.2 µM). AG110 is a highly selective inhibitor of pestivirus replication, with an EC50 of 1.2 µM against bovine viral diarrhea virus, targeting the viral RNA-dependent RNA polymerase.
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