Zibat Arne, Zhang Xiaoxiao, Dickmanns Antje, Stegmann Kim M, Dobbelstein Adrian W, Alachram Halima, Soliwoda Rebecca, Salinas Gabriela, Groß Uwe, Görlich Dirk, Kschischo Maik, Wollnik Bernd, Dobbelstein Matthias
Department of Human Genetics, University Medical Center Göttingen, 37073 Göttingen, Germany.
Department of Mathematics and Technology, University of Applied Sciences Koblenz, 53424 Remagen, Germany.
iScience. 2023 Aug 30;26(10):107786. doi: 10.1016/j.isci.2023.107786. eCollection 2023 Oct 20.
N4-hydroxycytidine (NHC), the active compound of the drug Molnupiravir, is incorporated into SARS-CoV-2 RNA, causing false base pairing. The desired result is an "error catastrophe," but this bears the risk of mutated virus progeny. To address this experimentally, we propagated the initial SARS-CoV-2 strain in the presence of NHC. Deep sequencing revealed numerous NHC-induced mutations and host-cell-adapted virus variants. The presence of the neutralizing nanobody Re5D06 selected for immune escape mutations, in particular p.E484K and p.F490S, which are key mutations of the Beta/Gamma and Omicron-XBB strains, respectively. With NHC treatment, nanobody resistance occurred two passages earlier than without. Thus, within the limitations of this purely study, we conclude that the combined action of Molnupiravir and a spike-neutralizing antagonist leads to the rapid emergence of escape mutants. We propose caution use and supervision when using Molnupiravir, especially when patients are still at risk of spreading virus.
N4-羟基胞苷（NHC）是药物莫努匹拉韦的活性成分，可掺入严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的核糖核酸（RNA）中，导致错误的碱基配对。预期结果是“错误灾难”，但这存在产生突变病毒后代的风险。为了通过实验解决这个问题，我们在NHC存在的情况下传代最初的SARS-CoV-2毒株。深度测序揭示了大量由NHC诱导的突变和适应宿主细胞的病毒变体。中和纳米抗体Re5D06的存在选择了免疫逃逸突变，特别是p.E484K和p.F490S，它们分别是贝塔/伽马毒株和奥密克戎-XBB毒株的关键突变。使用NHC治疗时，纳米抗体耐药性比不使用时提前两代出现。因此，在这项纯粹的研究的局限性内，我们得出结论，莫努匹拉韦和刺突蛋白中和拮抗剂的联合作用导致逃逸突变体迅速出现。我们建议在使用莫努匹拉韦时要谨慎并进行监测，尤其是当患者仍有传播病毒的风险时。
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