对霉酚酸和利巴韦林耐药的辛德毕斯病毒突变体

Sindbis virus mutants resistant to mycophenolic acid and ribavirin.

作者信息

Scheidel L M, Durbin R K, Stollar V

出版信息

Virology. 1987 May;158(1):1-7. doi: 10.1016/0042-6822(87)90230-3.

Abstract

Previous work from this laboratory has demonstrated a correlation between the inhibition by ribavirin (Rbv), mycophenolic acid (MPA), or 2-amino thiadiazole (TDA) of Sindbis virus replication in Aedes albopictus mosquito cells and a reduction in cellular GTP levels. This reduction in GTP results from the inhibition by these drugs of inosine monophosphate dehydrogenase (IMPDH), the first enzyme specific for the de novo synthesis of GMP. By serial passage of SV in A. albopictus cells in the presence of 25 microM MPA, we have now isolated viral mutants which are highly resistant not only to MPA but also to Rbv and TDA. For example, whereas 500 microM Rbv reduced the plaquing efficiency of SVSTD by at least 10(6)-fold, the same concentration of Rbv reduced the plaquing efficiency of the MPA-resistant mutants less than 5-fold. This is the first example of a viral mutant resistant to the antiviral compound Rbv.

摘要

该实验室之前的研究表明，利巴韦林（Rbv）、霉酚酸（MPA）或2-氨基噻二唑（TDA）对白纹伊蚊细胞中辛德毕斯病毒复制的抑制作用与细胞内GTP水平降低之间存在相关性。GTP水平的降低是由于这些药物抑制了肌苷单磷酸脱氢酶（IMPDH），这是GMP从头合成的第一种特异性酶。通过在25微摩尔MPA存在的情况下，将辛德毕斯病毒在白纹伊蚊细胞中连续传代，我们现在分离出了不仅对MPA高度耐药，而且对Rbv和TDA也高度耐药的病毒突变体。例如，500微摩尔的Rbv可使SVSTD的空斑形成效率降低至少10^6倍，而相同浓度的Rbv使MPA耐药突变体的空斑形成效率降低不到5倍。这是抗病毒化合物Rbv耐药病毒突变体的首个实例。