Combinatorial Regimens Augment Drug Monotherapy for SARS-CoV-2 Clearance in Mice

Ullah, I.; Escudie, F.; Scandale, I.; Gilani, Z.; Gendron-Lepage, G.; Gaudette, F.; Mowbray, C.; Fraisse, L.; Bazin, R.; Finzi, A.; Mothes, W.; Kumar, P.; Chatelain, E.; Uchil, P. D.

doi:10.1101/2023.05.31.543159

bioRxiv · 10.1101/2023.05.31.543159

Combinatorial Regimens Augment Drug Monotherapy for SARS-CoV-2 Clearance in Mice

Ullah, I.·Escudie, F.·Scandale, I.·Gilani, Z.·Gendron-Lepage, G.·Gaudette, F.·Mowbray, C.·Fraisse, L.·Bazin, R.·Finzi, A.·Mothes, W.·Kumar, P.·Chatelain, E.·Uchil, P. D.

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Abstract

Direct acting antivirals (DAAs) represent critical tools for combating SARS-CoV-2 variants of concern (VOCs) that evolve to escape 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 did not eliminate SARS-CoV-2 in mice. However, targeting two viral enzymes by combining molnupiravir with nirmatrelvir resulted in superior efficacy and virus clearance. Furthermore, combining molnupiravir with Caspase-1/4 inhibitor mitigated inflammation and lung pathology whereas combining molnupiravir with COVID-19 convalescent plasma yielded rapid virus clearance and 100% survival. Thus, our study provides insights into treatment efficacies of DAAs and other effective combinations to bolster COVID-19 therapeutic arsenal.

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Ullah, I., Escudie, F., Scandale, I., Gilani, Z., Gendron-Lepage, G., Gaudette, F., Mowbray, C., Fraisse, L., Bazin, R., Finzi, A., Mothes, W., Kumar, P., Chatelain, E., Uchil, P. D.. 2023-06-01. Combinatorial Regimens Augment Drug Monotherapy for SARS-CoV-2 Clearance in Mice. https://doi.org/10.1101/2023.05.31.543159

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