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10.1128/mbio.00869-22 http://scihub22266oqcxt.onion/10.1128/mbio.00869-22 35862764!9426535!35862764     free     free     free Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       mBio 2022 ; 13 (4): e0086922 Nephropedia Template TP {{tp|p=35862764|t=2022. Genetic Surveillance of SARS-CoV-2 M(pro) Reveals High Sequence and Structural Conservation Prior to the Introduction of Protease Inhibitor Paxlovid |pdf=|usr=}}{{35862764}} gab.com Text Genetic Surveillance of SARS-CoV-2 M(pro) Reveals High Sequence and Structural Conservation Prior to the Introduction of Protease Inhibitor Paxlovid JO: mBio http://www.kidney.de/pget.php?&tw=1&pmid=35862764 #FOAvip Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to represent a global health emergency as a highly transmissible, airborne virus. An important coronaviral drug target for treatment of COVID-19 is the conserved main protease (M(pro)). Nirmatrelvir is a potent M(pro) inhibitor and the antiviral component of Paxlovid. The significant viral sequencing effort during the ongoing COVID-19 pandemic represented a unique opportunity to assess potential nirmatrelvir escape mutations from emerging variants of SARS-CoV-2. To establish the baseline mutational landscape of M(pro) prior to the introduction of M(pro) inhibitors, M(pro) sequences and its cleavage junction regions were retrieved from ~4,892,000 high-quality SARS-CoV-2 genomes in the open-access Global Initiative on Sharing Avian Influenza Data (GISAID) database. Any mutations identified from comparison to the reference sequence (Wuhan-Hu-1) were catalogued and analyzed. Mutations at sites key to nirmatrelvir binding and protease functionality (e.g., dimerization sites) were still rare. Structural comparison of M(pro) also showed conservation of key nirmatrelvir contact residues across the extended Coronaviridae family (alpha-, beta-, and gamma-coronaviruses). Additionally, we showed that over time, the SARS-CoV-2 M(pro) enzyme remained under purifying selection and was highly conserved relative to the spike protein. Now, with the emergency use authorization (EUA) of Paxlovid and its expected widespread use across the globe, it is essential to continue large-scale genomic surveillance of SARS-CoV-2 M(pro) evolution. This study establishes a robust analysis framework for monitoring emergent mutations in millions of virus isolates, with the goal of identifying potential resistance to present and future SARS-CoV-2 antivirals. IMPORTANCE The recent authorization of oral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antivirals, such as Paxlovid, has ushered in a new era of the COVID-19 pandemic. The emergence of new variants, as well as the selective pressure imposed by antiviral drugs themselves, raises concern for potential escape mutations in key drug binding motifs. To determine the potential emergence of antiviral resistance in globally circulating isolates and its implications for the clinical response to the COVID-19 pandemic, sequencing of SARS-CoV-2 viral isolates before, during, and after the introduction of new antiviral treatments is critical. The infrastructure built herein for active genetic surveillance of M(pro) evolution and emergent mutations will play an important role in assessing potential antiviral resistance as the pandemic progresses and M(pro) inhibitors are introduced. We anticipate our framework to be the starting point in a larger effort for global monitoring of the SARS-CoV-2 M(pro) mutational landscape. Twit Text FOAVip Genetic Surveillance of SARS-CoV-2 M(pro) Reveals High Sequence and Structural Conservation Prior to the Introduction of Protease Inhibitor Paxlovid ????mBio http://www.kidney.de/pget.php?&tw=1&pmid=35862764 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=35862764 #FOAvip English Wikipedia <ref>{{Cite pmid|35862764}}</ref> Genetic Surveillance of SARS-CoV-2 M(pro) Reveals High Sequence and Structural Conservation Prior to the Introduction of Protease Inhibitor Paxlovid #MMPMID35862764 Lee JT; Yang Q; Gribenko A; Perrin BS Jr; Zhu Y; Cardin R; Liberator PA; Anderson AS; Hao L mBio 2022[Aug]; 13 (4): e0086922 PMID35862764show ga Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to represent a global health emergency as a highly transmissible, airborne virus. An important coronaviral drug target for treatment of COVID-19 is the conserved main protease (M(pro)). Nirmatrelvir is a potent M(pro) inhibitor and the antiviral component of Paxlovid. The significant viral sequencing effort during the ongoing COVID-19 pandemic represented a unique opportunity to assess potential nirmatrelvir escape mutations from emerging variants of SARS-CoV-2. To establish the baseline mutational landscape of M(pro) prior to the introduction of M(pro) inhibitors, M(pro) sequences and its cleavage junction regions were retrieved from ~4,892,000 high-quality SARS-CoV-2 genomes in the open-access Global Initiative on Sharing Avian Influenza Data (GISAID) database. Any mutations identified from comparison to the reference sequence (Wuhan-Hu-1) were catalogued and analyzed. Mutations at sites key to nirmatrelvir binding and protease functionality (e.g., dimerization sites) were still rare. Structural comparison of M(pro) also showed conservation of key nirmatrelvir contact residues across the extended Coronaviridae family (alpha-, beta-, and gamma-coronaviruses). Additionally, we showed that over time, the SARS-CoV-2 M(pro) enzyme remained under purifying selection and was highly conserved relative to the spike protein. Now, with the emergency use authorization (EUA) of Paxlovid and its expected widespread use across the globe, it is essential to continue large-scale genomic surveillance of SARS-CoV-2 M(pro) evolution. This study establishes a robust analysis framework for monitoring emergent mutations in millions of virus isolates, with the goal of identifying potential resistance to present and future SARS-CoV-2 antivirals. IMPORTANCE The recent authorization of oral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antivirals, such as Paxlovid, has ushered in a new era of the COVID-19 pandemic. The emergence of new variants, as well as the selective pressure imposed by antiviral drugs themselves, raises concern for potential escape mutations in key drug binding motifs. To determine the potential emergence of antiviral resistance in globally circulating isolates and its implications for the clinical response to the COVID-19 pandemic, sequencing of SARS-CoV-2 viral isolates before, during, and after the introduction of new antiviral treatments is critical. The infrastructure built herein for active genetic surveillance of M(pro) evolution and emergent mutations will play an important role in assessing potential antiviral resistance as the pandemic progresses and M(pro) inhibitors are introduced. We anticipate our framework to be the starting point in a larger effort for global monitoring of the SARS-CoV-2 M(pro) mutational landscape. |*COVID-19[MESH] |*SARS-CoV-2/genetics[MESH] |Animals[MESH] |Antiviral Agents/metabolism[MESH] |Coronavirus 3C Proteases[MESH] |Cysteine Endopeptidases/metabolism[MESH] |Drug Combinations[MESH] |Humans[MESH] |Lactams[MESH] |Leucine[MESH] |Nitriles[MESH] |Pandemics[MESH] |Proline[MESH] |Protease Inhibitors/chemistry/pharmacology[MESH] |Ritonavir[MESH]Genetic Surveillance of SARS-CoV-2 M(pro) Reveals High Sequence and St(epmc).pdf DeepDyve Pubget Overpricing