Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
J Med Chem. 2013 Dec 12;56(23):9403-14. doi: 10.1021/jm400653j. Epub 2013 Aug 26.
While mutation is the driving force behind evolution, most mutations are detrimental; therefore, elevating the mutation rate of a virus should diminish fitness. Because riboviruses and retroviruses have high mutation rates, a small increase in their mutation rates could exceed their threshold of viability. This approach, elevation of the viral mutation rate beyond the threshold of viability, extinction catastrophe or lethal mutagenesis, was proposed over a decade ago as a novel chemotherapeutic strategy. Extinction catastrophe induced by promutagenic nucleosides has been demonstrated in cell culture models, but most mutagens are carcinogenic and are poorly tolerated. Thus, clinical translation of viral mutagens has been difficult, casting doubt on the clinical viability of this strategy. This Perspective covers recent advances in the use of promutagenic nucleosides and the Vif-APOBEC interaction as chemotherapeutic strategies for targeting viral mutation rates.
虽然突变是进化的驱动力，但大多数突变都是有害的；因此，提高病毒的突变率应该会降低其适应性。由于核糖核酸病毒和逆转录病毒的突变率很高，因此它们的突变率只要稍有增加就可能超过其生存能力的阈值。十多年前，人们就曾提出将病毒的突变率提高到超过生存能力阈值，即灭绝性灾难或致死性诱变，作为一种新的化疗策略。在细胞培养模型中已经证明了促突变核苷引起的灭绝性灾难，但大多数诱变剂具有致癌性且耐受性差。因此，病毒诱变剂的临床转化一直很困难，这使得人们对该策略的临床可行性产生了怀疑。本观点综述了促突变核苷和 Vif-APOBEC 相互作用作为靶向病毒突变率的化疗策略的最新进展。
