Abstract：
This review considers antiviral nucleoside analog drugs, including ribavirin, favipiravir, and molnupiravir, which induce genome error catastrophe in SARS-CoV or SARS-CoV-2 via lethal mutagenesis as a mode of action. In vitro data indicate that molnupiravir may be 100 times more potent as an antiviral agent than ribavirin or favipiravir. Molnupiravir has recently demonstrated efficacy in a phase 3 clinical trial. Because of its anticipated global use, its relative potency, and the reported in vitro \"host\" cell mutagenicity of its active principle, β-d-N4-hydroxycytidine, we have reviewed the development of molnupiravir and its genotoxicity safety evaluation, as well as the genotoxicity profiles of three congeners, that is, ribavirin, favipiravir, and 5-(2-chloroethyl)-2\'-deoxyuridine. We consider the potential genetic risks of molnupiravir on the basis of all available information and focus on the need for additional human genotoxicity data and follow-up in patients treated with molnupiravir and similar drugs. Such human data are especially relevant for antiviral NAs that have the potential of permanently modifying the genomes of treated patients and/or causing human teratogenicity or embryotoxicity. We conclude that the results of preclinical genotoxicity studies and phase 1 human clinical safety, tolerability, and pharmacokinetics are critical components of drug safety assessments and sentinels of unanticipated adverse health effects. We provide our rationale for performing more thorough genotoxicity testing prior to and within phase 1 clinical trials, including human PIG-A and error corrected next generation sequencing (duplex sequencing) studies in DNA and mitochondrial DNA of patients treated with antiviral NAs that induce genome error catastrophe via lethal mutagenesis.
摘要：
这篇综述认为抗病毒核苷类似物药物，包括利巴韦林,favipiravir,和莫努比拉韦,通过致死诱变作为一种作用方式，在SARS-CoV或SARS-CoV-2中诱导基因组错误突变。体外数据表明，莫那普拉韦作为抗病毒剂的效力可能是利巴韦林或法维吡韦的100倍。Molnupiravir最近在3期临床试验中证明了疗效。由于其预期的全球使用，它的相对效力，及其活性成分的体外“宿主”细胞诱变性报道，β-d-N4-羟胞苷，我们回顾了莫努比拉韦的发展及其遗传毒性安全性评估，以及三种同源物的遗传毒性概况，也就是说,利巴韦林,favipiravir,和5-(2-氯乙基)-2'-脱氧尿苷。我们在所有可用信息的基础上考虑了莫那普拉韦的潜在遗传风险，并着重于对使用莫那普拉韦和类似药物治疗的患者的其他人类遗传毒性数据和随访的需求。此类人类数据与抗病毒NA特别相关,所述抗病毒NA具有永久修饰治疗患者的基因组和/或引起人类致畸性或胚胎毒性的潜力。我们得出的结论是，临床前遗传毒性研究和第一阶段人类临床安全性的结果，耐受性,和药代动力学是药物安全性评估的关键组成部分，也是未预期的不良健康影响的前哨指标。我们提供了在第一阶段临床试验之前和之内进行更彻底的遗传毒性测试的理由。包括在接受抗病毒NA治疗的患者的DNA和线粒体DNA中进行的人类PIG-A和错误校正的下一代测序（双重测序）研究，这些DNA通过致死诱变诱导基因组错误突变。
