Selection of a Thiazole Urea-Resistant Variant of Bovine Viral Diarrhoea Virus That Maps to the RNA-Dependent RNA Polymerase

• Published in: Antiviral chemistry & chemotherapy Vol. 13; no. 5; pp. 315 - 323
• Main Authors: King, Robert W, Scarnati, Helen T, Priestley, E Scott, De Lucca, Indawati, Bansal, Anu, Williams, J Kendall
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.10.2002; International Medical Press; Sage Publications Ltd
• Subjects: Amino acid substitution; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Bovine viral diarrhea virus; Cell Line; Diarrhea; Diarrhea Viruses, Bovine Viral - drug effects; Diarrhea Viruses, Bovine Viral - enzymology; Diarrhea Viruses, Bovine Viral - genetics; Diarrhea Viruses, Bovine Viral - physiology; DNA-directed RNA polymerase; Drug Resistance, Viral - genetics; Genomes; Inhibitory Concentration 50; Isoleucine; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Phenylalanine; Replication initiation; RNA polymerase; RNA Replicase - genetics; RNA, Viral - biosynthesis; RNA, Viral - genetics; RNA-directed RNA polymerase; Selection, Genetic; Thiazoles - chemistry; Thiazoles - pharmacology; Transcription; Transversion; Urea; Urea - analogs & derivatives; Urea - chemistry; Urea - pharmacology; Virus Replication - drug effects; bovine viral diarrhoea virus; RNA-dependent RNA polymerase; drug resistance; Pestivirus; Enzyme; Transferases; Thiazole derivatives; DNA-directed RNA polymerase; Biological activity; RNA- dependent RNA polymerase; Virus; Resistance; Urea; Nucleotidyltransferases; RNA synthesis; Bovine diarrhea virus; Antiviral; Replication; Mutation; Flaviviridae
• ISSN: 2040-2066; 0956-3202; 2040-2066
• DOI: 10.1177/095632020201300507

By passing wild type bovine viral diarrhoea virus (BVDV) in increasing concentrations of DPC-A69280–29, a thiazole urea class compound that inhibits BVDV replication, we were able to select several variants of BVDV that exhibited decreased susceptibility to this compound. When the non-structural genes of these variants were sequenced and compared with wild type, only one change was common to all the variants that also exhibited resistance to DPC-A69280–29 (>10-fold increase in IC50). This change was a T-to-A transversion at position 11198 of the BVDV genome, which would cause a predicted substitution of isoleucine for phenylalanine at amino acid 78 of the RNA-dependent RNA polymerase (RdRp). This substitution would occur in a region of the BVDV RdRp which has been proposed to be important for the formation of the RdRp homodimer that is essential for the activity of the enzyme. However, since DPC-69280-29 inhibits BVDV replication by interfering with the initiation of viral RNA synthesis, we discuss the possibility that this region of the BVDV RdRp also may play a role in the initiation process. Furthermore, since this region is located fairly close to the template RNA, we also propose that the role it plays may involve either template selection, stabilization or processivity.