Genetic conservation of SARS-CoV-2 RNA replication complex in globally circulating isolates and recently emerged variants from humans and minks suggests minimal pre-existing resistance to remdesivir.
Genetic conservation of SARS-CoV-2 RNA replication complex in globally circulating isolates and recently emerged variants from humans and minks suggests minimal pre-existing resistance to remdesivir.
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SARS-COV-2 RNA复制复合物在全球循环分离株中的遗传保护，最近从人类中出现了变体，这表明对Remdesivir的耐药性最小。
DOI：
10.1016/j.antiviral.2021.105033
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发表时间：
2021-04
影响因子：
7.6
通讯作者：
Svarovskaia E
中科院分区：
文献类型：
--
作者：
Martin R;Li J;Parvangada A;Perry J;Cihlar T;Mo H;Porter D;Svarovskaia E
Remdesivir（RDV）对SARS-CoV-2具有强效抗病毒活性，是目前唯一获批用于治疗COVID-19的药物。然而，目前对预先存在的对RDV的抗性的潜力以及SARS-CoV-2基因多样化的可能性知之甚少，这可能会影响RDV的效力，因为该病毒继续在全球传播。在这项研究中，对来自全球流行的临床分离株的> 90，000个SARS-CoV-2序列，包括最近出现的英国和南非变体的序列，以及来自水貂分离株的>300个序列进行了RNA复制复合体的遗传多样性分析。（nsp 7，nsp 8，nsp 10，nsp 12，nsp 13和nsp 14），重点是RNA依赖性RNA聚合酶（nsp 12），RDV的分子靶标。总体而言，在≥0.5%的分析序列中观察到低遗传变异，整个RNA复制复合物中仅存在12个氨基酸取代，其中观察到nsp 12 P323 L的总频率最高（82.2%），并随时间推移持续增加。在水貂分离株中也观察到RNA复制复合物的低序列变异。重要的是，在所有分析的序列中，仅在2个分离株（0.002%）中鉴定出先前在RDV存在下体外选择的冠状病毒Nsp 12突变。此外，在≥0.5%临床分离株（包括P323 L）中观察到的序列变异体中，均未位于已确定的聚合酶活性位点或RDV抑制机制的关键位点附近。总之，随着时间的推移和在最近出现的SARS-CoV-2变异体中观察到的RNA复制复合物的低多样性和高遗传稳定性表明，预先存在的SARS-CoV-2对RDV的抗性的全球风险最小。
Remdesivir (RDV) exhibits potent antiviral activity against SARS-CoV-2 and is currently the only drug approved for the treatment of COVID-19. However, little is currently known about the potential for pre-existing resistance to RDV and the possibility of SARS-CoV-2 genetic diversification that might impact RDV efficacy as the virus continue to spread globally. In this study, >90,000 SARS-CoV-2 sequences from globally circulating clinical isolates, including sequences from recently emerged United Kingdom and South Africa variants, and >300 from mink isolates were analyzed for genetic diversity in the RNA replication complex (nsp7, nsp8, nsp10, nsp12, nsp13, and nsp14) with a focus on the RNA-dependent RNA polymerase (nsp12), the molecular target of RDV. Overall, low genetic variation was observed with only 12 amino acid substitutions present in the entire RNA replication complex in ≥0.5% of analyzed sequences with the highest overall frequency (82.2%) observed for nsp12 P323L that consistently increased over time. Low sequence variation in the RNA replication complex was also observed among the mink isolates. Importantly, the coronavirus Nsp12 mutations previously selected in vitro in the presence of RDV were identified in only 2 isolates (0.002%) within all the analyzed sequences. In addition, among the sequence variants observed in ≥0.5% clinical isolates, including P323L, none were located near the established polymerase active site or sites critical for the RDV mechanism of inhibition. In summary, the low diversity and high genetic stability of the RNA replication complex observed over time and in the recently emerged SARS-CoV-2 variants suggests a minimal global risk of pre-existing SARS-CoV-2 resistance to RDV.
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