Ullah etal_ISCIENCE-D-23-05286: Bioluminescence Imaging Reveals Enhanced SARS-CoV-2 Clearance in Mice with Combinatorial Regimens

Direct acting antivirals (DAAs) represent critical tools for combating SARS-CoV-2 variants of concern (VOCs) that have escaped vaccine-elicited spike-based immunity and future coronaviruses with pandemic potential. Here, we used bioluminescence imaging to evaluate therapeutic efficacy of DAAs that target SARS-CoV-2 RNA-dependent RNA polymerase (favipiravir, molnupiravir) or Main protease (nirmatrelvir) against Delta or Omicron VOCs in K18-hACE2 mice. Nirmatrelvir displayed the best efficacy followed by molnupiravir and favipiravir in suppressing viral loads in the lung. Unlike neutralizing antibody treatment, DAA monotherapy regimens did not eradicate SARS-CoV-2 in mice but combining molnupiravir with nirmatrelvir exhibited superior additive efficacy and led to virus clearance. Furthermore, combining molnupiravir with Caspase-1/4 inhibitor mitigated inflammation and lung pathology whereas combining molnupiravir with COVID-19 convalescent plasma demonstrated synergy, rapid virus clearance and 100% survival. Thus, our study provides insights into in vivo treatment efficacies of DAAs and other effective combinations to bolster COVID-19 therapeutic arsenal. The excel files are arranged figure wise and contain the raw data used to generate figures shown in the manuscript "Ullah etal_ISCIENCE-D-23-05286"直接作用抗病毒药物（Direct acting antivirals, DAAs）是对抗逃逸疫苗诱导的刺突蛋白免疫的新冠病毒（SARS-CoV-2）关切变异株（Variants of Concern, VOCs）以及未来具备大流行潜力的冠状病毒的关键防控工具。本研究采用生物发光成像技术，评估了靶向新冠病毒RNA依赖的RNA聚合酶（法匹拉韦（favipiravir）、莫努匹拉韦（molnupiravir））或主蛋白酶（奈玛特韦（nirmatrelvir））的DAAs，对K18人血管紧张素转换酶2（hACE2）转基因小鼠体内Delta或Omicron关切变异株的治疗效果。在抑制小鼠肺部病毒载量方面，奈玛特韦疗效最佳，其次为莫努匹拉韦与法匹拉韦。与中和抗体治疗不同，DAAs单药治疗方案无法清除小鼠体内的新冠病毒，但将莫努匹拉韦与奈玛特韦联合使用时，展现出更优的叠加疗效，可实现病毒清除。此外，将莫努匹拉韦与半胱天冬酶-1/4（Caspase-1/4）抑制剂联合使用，可减轻炎症反应与肺部病理损伤；而莫努匹拉韦联合新冠康复者血浆则展现出协同效应，可快速清除病毒并使小鼠达到100%存活率。本研究阐明了DAAs及其有效联合疗法的体内治疗效果，可为扩充新冠治疗武器库提供参考依据。本研究附带的Excel文件按图表分类整理，包含生成论文《Ullah etal_ISCIENCE-D-23-05286》中各类图表所用的原始数据。