Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

The Combination of Molnupiravir with Nirmatrelvir or GC376 has a Synergic role in the Inhibition of SARS-CoV-2 Replication in Vitro

Anna Gidari
* ORCID logo ,
Samuele Sabbatini
,
Elisabetta Schiaroli
,
Sabrina Bastianelli
ORCID logo ,
Sara Pierucci
ORCID logo ,
Chiara Busti
,
Lucia Comez
ORCID logo ,
Valeria Libera
,
Antonio Macchiarulo
ORCID logo ,
Alessandro Paciaroni
,
Ilaria Vicenti
,
Maurizio Zazzi
,
Daniela Francisci
Version 1 : Received: 12 June 2022 / Approved: 20 June 2022 / Online: 20 June 2022 (10:57:26 CEST)

How to cite: Gidari, A.; Sabbatini, S.; Schiaroli, E.; Bastianelli, S.; Pierucci, S.; Busti, C.; Comez, L.; Libera, V.; Macchiarulo, A.; Paciaroni, A.; Vicenti, I.; Zazzi, M.; Francisci, D. The Combination of Molnupiravir with Nirmatrelvir or GC376 has a Synergic role in the Inhibition of SARS-CoV-2 Replication in Vitro. Preprints 2022, 2022060272. https://doi.org/10.20944/preprints202206.0272.v1 Gidari, A.; Sabbatini, S.; Schiaroli, E.; Bastianelli, S.; Pierucci, S.; Busti, C.; Comez, L.; Libera, V.; Macchiarulo, A.; Paciaroni, A.; Vicenti, I.; Zazzi, M.; Francisci, D. The Combination of Molnupiravir with Nirmatrelvir or GC376 has a Synergic role in the Inhibition of SARS-CoV-2 Replication in Vitro. Preprints 2022, 2022060272. https://doi.org/10.20944/preprints202206.0272.v1

Abstract

Introduction: The development of effective vaccines has partially mitigated the trend of the SARS-CoV-2 pandemic, however, the need for orally available antiviral drugs persists. This study aims to investigate the activity of molnupiravir in combination with nirmatrelvir or GC376 on SARS-CoV-2 to verify the synergistic effect. Methods: The SARS-CoV-2 strains 20A.EU, BA.1 and BA.2 were used to infect Vero E6 in presence of antiviral compounds alone or in combinations using 5 two-fold serial dilution of compound concentrations ≤EC90. After 48 and 72 h post-infection, viability was performed using MTT reduction assay. Supernatants were collected for plaque-assay titration. All experiments were conducted three times and in triplicate. The synergistic score was calculated using Synergy Finder version 2. Results: All compounds reached micromolar EC90. Molnupiravir and GC376 showed a synergistic activity at 48 h with an HSA score of 19.33 (p<0.0001) and an additive activity at 72 h with an HSA score of 8.61 (p<0.0001). Molnupiravir and nirmatrelvir showed a synergistic activity both at 48 h and 72 h with an HSA score of 14.2 (p=0.01) and 13.08 (p<0.0001), respectively. Conclusion: Molnupiravir associated with one of the two protease-inhibitors nirmatrelvir and GC376 showed good additive-synergic activity in vitro.

Keywords

COVID-19; SARS-CoV-2; molnupiravir; nirmatrelvir; GC376; PF-07321332; variant; synergy; an-tiviral

Subject

Medicine and Pharmacology, Pulmonary and Respiratory Medicine

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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