Selection of a thiazole urea-resistant variant of bovine viral diarrhoea virus that maps to the RNA-dependent RNA polymerase.
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.
King
Robert W
RW
The Experimental Station, Bristol-Myers Squibb, Wilmington, Del., USA. shenking@msn.com
Scarnati
Helen T
HT
Priestley
E Scott
ES
De Lucca
Indawati
I
Bansal
Anu
A
Williams
J Kendall
JK
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D001908:Diarrhea Viruses, Bovine Viral / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics* / Q000502:physiology; D024882:Drug Resistance, Viral / Q000235:genetics*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D012367:RNA, Viral / Q000096:biosynthesis / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics*; D012641:Selection, Genetic; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; C479068:DPC A69280-29; D012367:RNA, Viral; D013844:Thiazoles; D014508:Urea; D012324:RNA-Dependent RNA Polymerase