Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland.
Int J Mol Sci. 2022 Jul 27;23(15):8302. doi: 10.3390/ijms23158302.
The current COVID-19 pandemic has highlighted the necessity of more efficient antiviral compounds. The antiviral efficacy of adenosine-based analogs, the main repurposed drugs for SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibition, is mainly assessed through in vitro or cell-free polymerization assays, under arbitrary conditions that do not reflect the physiological environment. We show that SARS-CoV-2 RdRp inhibition efficiency of remdesivir and cordycepin, two common adenosine analogs, is influenced by endogenous adenosine level, and that the current clinically approved concentrations for COVID-19 treatment are suboptimal for effective RdRp inhibition. Furthermore, we identified GTP as the rate-limiting nucleotide of SARS-CoV-2 replication. Our results demonstrate that nucleotide sensitivity of the RdRp complex and competition of nucleoside analog drugs against endogenous concentrations of nucleotides are crucial elements to be considered when designing new SARS-CoV-2 antiviral compounds.
当前的 COVID-19 大流行凸显了更高效的抗病毒化合物的必要性。基于腺苷的类似物的抗病毒功效，是主要的重新利用药物用于抑制 SARS-CoV-2 RNA 依赖性 RNA 聚合酶（RdRp），主要通过体外或无细胞聚合测定来评估，这些测定在任意条件下进行，这些条件并不能反映生理环境。我们表明，两种常见的腺苷类似物瑞德西韦和虫草素对 SARS-CoV-2 RdRp 的抑制效率受到内源性腺苷水平的影响，并且当前用于 COVID-19 治疗的临床批准浓度对于有效抑制 RdRp 来说并不理想。此外，我们确定 GTP 是 SARS-CoV-2 复制的限速核苷酸。我们的结果表明，RdRp 复合物对核苷酸的敏感性以及核苷类似物药物与内源性核苷酸浓度的竞争，是设计新型 SARS-CoV-2 抗病毒化合物时需要考虑的关键因素。
