Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors

Seyed Arad Moghadasi, Emmanuel Heilmann, Ahmed Magdy Khalil, Christina Nnabuife, Fiona L. Kearns, Chengjin Ye, Sofia N. Moraes, Francesco Costacurta, Morgan A. Esler, Hideki Aihara, Dorothee von Laer, Luis Martinez-Sobrido, Timothy Palzkill, Rommie E. Amaro, Reuben S. Harris

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


Vaccines and drugs have helped reduce disease severity and blunt the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, ongoing virus transmission, continuous evolution, and increasing selective pressures have the potential to yield viral variants capable of resisting these interventions. Here, we investigate the susceptibility of natural variants of the main protease [Mpro; 3C-like protease (3CLpro)] of SARSCoV-2 to protease inhibitors. Multiple single amino acid changes in Mpro confer resistance to nirmatrelvir (the active component of Paxlovid). An additional clinical-stage inhibitor, ensitrelvir (Xocova), shows a different resistance mutation profile. Importantly, phylogenetic analyses indicate that several of these resistant variants have pre-existed the introduction of these drugs into the human population and are capable of spreading. These results encourage the monitoring of resistance variants and the development of additional protease inhibitors and other antiviral drugs with different mechanisms of action and resistance profiles for combinatorial therapy.

Original languageEnglish (US)
Article numbereade8778
JournalScience Advances
Issue number13
StatePublished - Mar 29 2023

ASJC Scopus subject areas

  • General


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