King Robert W, Scarnati Helen T, Priestley E Scott, De Lucca Indawati, Bansal Anu, Williams J Kendall
The Experimental Station, Bristol-Myers Squibb, Wilmington, Del., USA.
Antivir Chem Chemother. 2002 Sep;13(5):315-23. 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.
通过在浓度不断增加的DPC-A69280-29（一种抑制牛病毒性腹泻病毒（BVDV）复制的噻唑脲类化合物）中传代野生型BVDV，我们能够筛选出几种对该化合物敏感性降低的BVDV变体。对这些变体的非结构基因进行测序并与野生型进行比较时，所有对DPC-A69280-29表现出抗性（IC50增加>10倍）的变体都有一个共同变化。这个变化是BVDV基因组第11198位的T到A颠换，这将导致在RNA依赖性RNA聚合酶（RdRp）的第78位氨基酸处预测异亮氨酸取代苯丙氨酸。这种取代将发生在BVDV RdRp的一个区域，该区域被认为对形成酶活性所必需的RdRp同型二聚体很重要。然而，由于DPC-69280-29通过干扰病毒RNA合成的起始来抑制BVDV复制，我们讨论了BVDV RdRp的这个区域也可能在起始过程中起作用的可能性。此外，由于该区域相当靠近模板RNA，我们还提出它所起的作用可能涉及模板选择、稳定或持续性。
