PDF(Pubmed)
Abstract：
During the ongoing pandemic, providing treatment consisting of effective, low-cost oral antiviral drugs at an early stage of SARS-CoV-2 infection has been a priority for controlling COVID-19. Although Paxlovid and molnupiravir have received emergency approval from the FDA, some side effect concerns have emerged, and the possible oral agents are still limited, resulting in optimized drug development becoming an urgent requirement. An oral remdesivir derivative, VV116, has been reported to have promising antiviral effects against SARS-CoV-2 and positive therapeutic outcomes in clinical trials. However, whether VV116 has broad-spectrum anti-coronavirus activity and potential synergy with other drugs is not clear. Here, we uncovered the broad-spectrum antiviral potency of VV116 against SARS-CoV-2 variants of concern (VOCs), HCoV-OC43, and HCoV-229E in various cell lines. In vitro drug combination screening targeted RdRp and proteinase, highlighting the synergistic effect of VV116 and nirmatrelvir on HCoV-OC43 and SARS-CoV-2. When co-administrated with ritonavir, the combination of VV116 and nirmatrelvir showed significantly enhanced antiviral potency with noninteracting pharmacokinetic properties in mice. Our findings will facilitate clinical treatment with VV116 or VV116+nirmatrelvir combination to fight coronavirus infection.
摘要：
在持续的大流行期间，提供有效的治疗，在SARS-CoV-2感染的早期阶段，低成本的口服抗病毒药物一直是控制COVID-19的优先事项。尽管Paxlovid和Molnupiravir已获得FDA的紧急批准，一些副作用的担忧已经出现，可能的口服药物仍然有限，从而优化药物开发成为迫切需要。一种口服雷得西韦衍生物,据报道，VV116对SARS-CoV-2具有有希望的抗病毒作用，并且在临床试验中具有积极的治疗效果。然而,VV116是否具有广谱抗冠状病毒活性以及与其他药物的潜在协同作用尚不清楚.这里,我们发现了VV116对SARS-CoV-2变体（VOCs）的广谱抗病毒效力，各种细胞系中的HCoV-OC43和HCoV-229E。体外药物联合筛选靶向RdRp和蛋白酶，强调VV116和尼马特雷韦对HCoV-OC43和SARS-CoV-2的协同作用。当与利托那韦共同管理时，VV116和nirmatrelvir的组合在小鼠中显示出显著增强的抗病毒效力和非相互作用的药代动力学特性.我们的发现将有助于VV116或VV116+nirmatrelvir组合的临床治疗来对抗冠状病毒感染。
