Favipiravir is a broad-spectrum inhibitor of viral RNA-dependent RNA polymerase (RdRp) currently being used to manage COVID-19. Accumulation of mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RdRp may facilitate antigenic drift, generating favipiravir resistance. Focussing on the chain-termination mechanism utilized by favipiravir, we used high-throughput interface-based protein design to generate > 100 000 designs of the favipiravir-binding site of RdRp and identify mutational hotspots. We identified several single-point mutants and designs having a sequence identity of 97%–98% with wild-type RdRp, suggesting that SARS-CoV-2 can develop favipiravir resistance with few mutations. Out of 134 mutations documented in the CoV-GLUE database, 63 specific mutations were already predicted as resistant in our calculations, thus attaining ˜ 47% correlation with the sequencing data. These findings improve our understanding of the potential signatures of adaptation in SARS-CoV-2 against favipiravir.

中文翻译：

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SARS-CoV-2 RNA依赖性RNA聚合酶中法匹拉韦结合位点的基于界面设计揭示了赋予链终止抗性的突变

Favipiravir 是一种病毒 RNA 依赖性 RNA 聚合酶 (RdRp) 的广谱抑制剂，目前用于治疗 COVID-19。严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) RdRp 突变的积累可能会促进抗原漂移，从而产生法匹拉韦耐药性。着眼于 favipiravir 使用的链终止机制，我们使用基于高通量界面的蛋白质设计来生成 > 100 000 个 RdRp 的 favipiravir 结合位点设计并识别突变热点。我们鉴定了几个与野生型 RdRp 具有 97%–98% 序列同一性的单点突变体和设计，这表明 SARS-CoV-2 可以在很少突变的情况下产生法匹拉韦耐药性。在 CoV-GLUE 数据库中记录的 134 个突变中，在我们的计算中已经预测 63 个特定突变具有抗性，从而与测序数据获得约 47% 的相关性。这些发现提高了我们对 SARS-CoV-2 适应法匹拉韦的潜在特征的理解。