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
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 [M pro ; 3C-like protease (3CL pro )] of SARS-CoV-2 to protease inhibitors. Multiple single amino acid changes in M pro 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.
Supplementary Materials This PDF file includes: Figs. S1 to S12 Tables S1 to S3 Competing interests: R. The other authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. The ciscleaving VSV-based M pro assay can be provided by D.v.L. pending scientific review and a completed material transfer agreement. Requests for the ciscleaving VSV-based M pro assay should be submitted to D.v.L. (dorothee.von-laer@i-med.ac. at). Requests for the transfection-based gain-of-signal M pro system should be submitted to R.S.H. (rsh@uthscsa.edu).
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