Pardes Biosciences, Inc. , Carlsbad, California, USA.
Vanderbilt University Medical Center , Nashville, Tennessee, USA.
Antimicrob Agents Chemother. 2023 Nov 15;67(11):e0084023. doi: 10.1128/aac.00840-23. Epub 2023 Oct 6.
The unprecedented scale of the COVID-19 pandemic and the rapid evolution of SARS-CoV-2 variants underscore the need for broadly active inhibitors with a high barrier to resistance. The coronavirus main protease (M) is an essential cysteine protease required for viral polyprotein processing and is highly conserved across human coronaviruses. Pomotrelvir is a novel M inhibitor that has recently completed a phase 2 clinical trial. In this report, we demonstrated that pomotrelvir is a potent competitive inhibitor of SARS-CoV-2 M with high selectivity against human proteases. In the enzyme assay, pomotrelvir is also active against M proteins derived from human coronaviruses CoV-229E, CoV-OC43, CoV-HKU1, CoV-NL63, MERS, and SARS-CoV. In cell-based SARS-CoV-2 replicon and SARS-CoV-2 infection assays, pomotrelvir has shown potent inhibitory activity and is broadly active against SARS-CoV-2 clinical isolates including Omicron variants. Many resistance substitutions of the M inhibitor nirmatrelvir confer cross-resistance to pomotrelvir, consistent with the finding from our enzymatic analysis that pomotrelvir and nirmatrelvir compete for the same binding site. In a SARS-CoV-2 infection assay, pomotrelvir is additive when combined with remdesivir or molnupiravir, two nucleoside analogs targeting viral RNA synthesis. In conclusion, our results from the characterization of pomotrelvir antiviral activity support its further clinical development as an alternative COVID-19 therapeutic option.
新型冠状病毒肺炎大流行的空前规模和 SARS-CoV-2 变异株的快速进化，凸显了对具有高耐药屏障的广泛有效的抑制剂的需求。冠状病毒主蛋白酶（M）是一种必需的半胱氨酸蛋白酶，是病毒多蛋白加工所必需的，在人类冠状病毒中高度保守。Pomotrelvir 是一种新型的 M 抑制剂，最近完成了 2 期临床试验。在本报告中，我们证明了 pomotrelvir 是一种有效的 SARS-CoV-2 M 竞争性抑制剂，对人蛋白酶具有很高的选择性。在酶测定中，pomotrelvir 对源自人类冠状病毒 229E、OC43、HKU1、NL63、MERS 和 SARS-CoV 的 M 蛋白也具有活性。在基于细胞的 SARS-CoV-2 复制子和 SARS-CoV-2 感染测定中，pomotrelvir 表现出有效的抑制活性，对包括奥密克戎变异株在内的 SARS-CoV-2 临床分离株具有广泛的活性。M 抑制剂奈玛特韦的许多耐药替代物赋予对 pomotrelvir 的交叉耐药性，这与我们的酶分析结果一致，即 pomotrelvir 和奈玛特韦竞争相同的结合位点。在 SARS-CoV-2 感染测定中，pomotrelvir 与瑞德西韦或莫努匹韦联合使用时具有相加作用，瑞德西韦或莫努匹韦是两种靶向病毒 RNA 合成的核苷类似物。总之，我们对 pomotrelvir 抗病毒活性的表征结果支持其进一步的临床开发，作为一种替代 COVID-19 的治疗选择。
