RT Journal Article SR Electronic T1 Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.08.07.503099 DO 10.1101/2022.08.07.503099 A1 Seyed Arad Moghadasi A1 Emmanuel Heilmann A1 Ahmed Magdy Khalil A1 Christina Nnabuife A1 Fiona L. Kearns A1 Chengjin Ye A1 Sofia N. Moraes A1 Francesco Costacurta A1 Morgan A. Esler A1 Hideki Aihara A1 Dorothee von Laer A1 Luis Martinez-Sobrido A1 Timothy Palzkill A1 Rommie E. Amaro A1 Reuben S. Harris YR 2022 UL http://biorxiv.org/content/early/2022/12/26/2022.08.07.503099.abstract AB Vaccines and drugs have helped reduce disease severity and blunt the spread of 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/3CLpro) of SARS-CoV-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.One Sentence Summary Resistance to protease inhibitor drugs, nirmatrelvir (Paxlovid) and ensitrelvir (Xocova), exists in SARS-CoV-2 variants in the human population.Competing Interest StatementDvL is founder of ViraTherapeutics GmbH and serves as a scientific advisor to Boehringer Ingelheim and Pharma KG. The other authors have no competing interests to declare.