TY - JOUR T1 - Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors JF - bioRxiv DO - 10.1101/2022.08.07.503099 SP - 2022.08.07.503099 AU - Seyed Arad Moghadasi AU - Emmanuel Heilmann AU - Ahmed Magdy Khalil AU - Christina Nnabuife AU - Fiona L. Kearns AU - Chengjin Ye AU - Sofia N. Moraes AU - Francesco Costacurta AU - Morgan A. Esler AU - Hideki Aihara AU - Dorothee von Laer AU - Luis Martinez-Sobrido AU - Timothy Palzkill AU - Rommie E. Amaro AU - Reuben S. Harris Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/12/26/2022.08.07.503099.abstract N2 - 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. ER -