RT Journal Article SR Electronic T1 Comparative study of a 3CLpro inhibitor and remdesivir against both major SARS-CoV-2 clades in human airway models JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.08.28.272880 DO 10.1101/2020.08.28.272880 A1 Maren de Vries A1 Adil S Mohamed A1 Rachel A Prescott A1 Ana M Valero-Jimenez A1 Ludovic Desvignes A1 Rebecca O’Connor A1 Claire Steppan A1 Annaliesa S. Anderson A1 Joseph Binder A1 Meike Dittmann YR 2020 UL http://biorxiv.org/content/early/2020/08/28/2020.08.28.272880.abstract AB Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of Coronavirus Disease 2019 (COVID-19), a pandemic that has claimed over 700,000 human lives. The only SARS-CoV-2 antiviral, for emergency use, is remdesivir, targeting the viral polymerase complex. PF-00835231 is a pre-clinical lead compound with an alternate target, the main SARS-CoV-2 protease 3CLpro (Mpro). Here, we perform a comparative analysis of PF-00835231 and remdesivir in A549+ACE2 cells, using isolates of two major SARS-CoV-2 clades. PF-00835231 is antiviral for both clades, and, in this assay, statistically more potent than remdesivir. A time-of-drug-addition approach delineates the timing of early SARS-CoV-2 life cycle steps and validates PF-00835231’s time of action. Both PF-00835231 and remdesivir potently inhibit SARS-CoV-2 in human polarized airway epithelial cultures. Thus, our study provides in vitro evidence for the potential of PF-00835231 as an effective antiviral for SARS-CoV-2, addresses concerns from non-human in vitro models, and supports further studies with this compound.Competing Interest StatementM. D. received a contract from Pfizer Inc. to support the studies reported herein. These authors are employees of Pfizer Inc. and hold stock in Pfizer Inc: Joseph Binder, Annaliesa Anderson, Claire Steppan, Rebecca OConnor.