OyaGen, Inc., Rochester, NY, USA.
Department of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt, Germany.
Antiviral Res. 2023 Oct;218:105716. doi: 10.1016/j.antiviral.2023.105716. Epub 2023 Sep 9.
Sangivamycin (S) is an adenosine (A) nucleoside analog with low nanomolar antiviral activity against SARS-CoV-2 in vitro. Previously, low nanomolar antiviral efficacy was revealed when tested against multiple viral variants in several cell types. SARS-CoV-2 RNA isolated from live virus infected cells and the virions released from these cells was analyzed by mass spectrometry (MS) for S incorporation. Dose-dependent incorporation occurred up to 1.8 S per 1,000 nucleotides (49 S per genome) throughout the viral genomes isolated from both infected cells and viral particles, but this incorporation did not change the viral mutation rate. In contrast, host mRNA, affinity purified from the same infected and treated cells, contained little or no S. Sangivamycin triphosphate (STP) was synthesized to evaluate its incorporation into RNA by recombinant SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) under defined in vitro conditions. SARS-CoV-2 RdRp showed that S was not a chain terminator and S containing oligonucleotides templated as A. Though the antiviral mechanism remains to be determined, the data suggests that SARS-CoV-2 RdRp incorporates STP into SARS-CoV-2 RNA, which does not significantly impair viral RNA synthesis or the mutation rate.
桑吉霉素（S）是一种腺苷（A）核苷类似物，具有体外抗 SARS-CoV-2 的低纳摩尔抗病毒活性。此前，在几种细胞类型中针对多种病毒变异株进行测试时，发现其具有低纳摩尔抗病毒功效。用质谱（MS）分析从活病毒感染细胞中分离的 SARS-CoV-2 RNA 和从这些细胞释放的病毒粒子，以确定 S 的掺入情况。在从受感染细胞和病毒粒子分离的整个病毒基因组中，S 的掺入量高达每个千核苷酸 1.8 S（每个基因组 49 S），呈剂量依赖性，但这种掺入不会改变病毒的突变率。相比之下，从相同受感染和处理的细胞中亲和纯化的宿主 mRNA 几乎不含 S。合成桑吉霉素三磷酸（STP）以评估其在重组 SARS-CoV-2 RNA 依赖性 RNA 聚合酶（RdRp）下在定义的体外条件下掺入 RNA 的情况。SARS-CoV-2 RdRp 表明 S 不是链终止子，并且 S 含有模板化的 A 寡核苷酸。尽管抗病毒机制仍有待确定，但数据表明 SARS-CoV-2 RdRp 将 STP 掺入 SARS-CoV-2 RNA 中，这不会显著损害病毒 RNA 合成或突变率。
