Crystal structures of main protease ($ M^{pro} $) mutants of SARS-CoV-2 variants bound to PF-07304814

Abstract There is an urgent need to develop effective antiviral drugs to prevent the viral infection caused by constantly circulating SARS-CoV-2 as well as its variants. The main protease ($ M^{pro} $) of SARS-CoV-2 is a salient enzyme that plays a vital role in viral replication and serves as a fas...
Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Jiang, Haihai [verfasserIn] Zou, Xiaofang Zeng, Pei Zeng, Xiangyi Zhou, Xuelan Wang, Jie Zhang, Jin Li, Jian

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	SARS-CoV-2 Variant Main protease Inhibitor PF-07304814

Anmerkung:	© The Author(s) 2023

Übergeordnetes Werk:	Enthalten in: Molecular biomedicine - Cham : Springer Nature Switzerland, 2020, 4(2023), 1 vom: 03. Aug.
Übergeordnetes Werk:	volume:4 ; year:2023 ; number:1 ; day:03 ; month:08

Links:	Volltext

DOI / URN:	10.1186/s43556-023-00134-2

Katalog-ID:	SPR052621839

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520			\|a Abstract There is an urgent need to develop effective antiviral drugs to prevent the viral infection caused by constantly circulating SARS-CoV-2 as well as its variants. The main protease ($ M^{pro} $) of SARS-CoV-2 is a salient enzyme that plays a vital role in viral replication and serves as a fascinating therapeutic target. PF-07304814 is a covalent inhibitor targeting SARS-CoV-2 $ M^{pro} $ with favorable inhibition potency and drug-like properties, thus making it a promising drug candidate for the treatment of COVID-19. We previously solved the structure of PF-07304814 in complex with SARS-CoV-2 $ M^{pro} $. However, the binding modes of PF-07304814 with $ M^{pro} $s from evolving SARS-CoV-2 variants is under-determined. In the current study, we expressed six $ M^{pro} $ mutants (G15S, K90R, M49I, S46F, V186F, and Y54C) that have been identified in Omicron variants including the recently emerged XBB.1.16 subvariant and solved the crystal structures of PF-07304814 bound to $ M^{pro} $ mutants. Structural analysis provided insight into the key molecular determinants responsible for the interaction between PF-07304814 and these mutant $ M^{pro} $s. Patterns for PF-07304814 to bind with these investigated $ M^{pro} $ mutants and the wild-type $ M^{pro} $ are generally similar but with some differences as revealed by detailed structural comparison. Structural insights presented in this study will inform the development of novel drugs against SARS-CoV-2 and the possible conformation changes of $ M^{pro} $ mutants when bound to an inhibitor.
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allfields	10.1186/s43556-023-00134-2 doi (DE-627)SPR052621839 (SPR)s43556-023-00134-2-e DE-627 ger DE-627 rakwb eng Jiang, Haihai verfasserin (orcid)0000-0002-1895-3040 aut Crystal structures of main protease ($ M^{pro} $) mutants of SARS-CoV-2 variants bound to PF-07304814 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract There is an urgent need to develop effective antiviral drugs to prevent the viral infection caused by constantly circulating SARS-CoV-2 as well as its variants. The main protease ($ M^{pro} $) of SARS-CoV-2 is a salient enzyme that plays a vital role in viral replication and serves as a fascinating therapeutic target. PF-07304814 is a covalent inhibitor targeting SARS-CoV-2 $ M^{pro} $ with favorable inhibition potency and drug-like properties, thus making it a promising drug candidate for the treatment of COVID-19. We previously solved the structure of PF-07304814 in complex with SARS-CoV-2 $ M^{pro} $. However, the binding modes of PF-07304814 with $ M^{pro} $s from evolving SARS-CoV-2 variants is under-determined. In the current study, we expressed six $ M^{pro} $ mutants (G15S, K90R, M49I, S46F, V186F, and Y54C) that have been identified in Omicron variants including the recently emerged XBB.1.16 subvariant and solved the crystal structures of PF-07304814 bound to $ M^{pro} $ mutants. Structural analysis provided insight into the key molecular determinants responsible for the interaction between PF-07304814 and these mutant $ M^{pro} $s. Patterns for PF-07304814 to bind with these investigated $ M^{pro} $ mutants and the wild-type $ M^{pro} $ are generally similar but with some differences as revealed by detailed structural comparison. Structural insights presented in this study will inform the development of novel drugs against SARS-CoV-2 and the possible conformation changes of $ M^{pro} $ mutants when bound to an inhibitor. SARS-CoV-2 (dpeaa)DE-He213 Variant (dpeaa)DE-He213 Main protease (dpeaa)DE-He213 Inhibitor (dpeaa)DE-He213 PF-07304814 (dpeaa)DE-He213 Zou, Xiaofang aut Zeng, Pei aut Zeng, Xiangyi aut Zhou, Xuelan aut Wang, Jie aut Zhang, Jin aut Li, Jian aut Enthalten in Molecular biomedicine Cham : Springer Nature Switzerland, 2020 4(2023), 1 vom: 03. Aug. (DE-627)1726726452 (DE-600)3033856-6 2662-8651 nnns volume:4 year:2023 number:1 day:03 month:08 https://dx.doi.org/10.1186/s43556-023-00134-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 4 2023 1 03 08
spelling	10.1186/s43556-023-00134-2 doi (DE-627)SPR052621839 (SPR)s43556-023-00134-2-e DE-627 ger DE-627 rakwb eng Jiang, Haihai verfasserin (orcid)0000-0002-1895-3040 aut Crystal structures of main protease ($ M^{pro} $) mutants of SARS-CoV-2 variants bound to PF-07304814 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract There is an urgent need to develop effective antiviral drugs to prevent the viral infection caused by constantly circulating SARS-CoV-2 as well as its variants. The main protease ($ M^{pro} $) of SARS-CoV-2 is a salient enzyme that plays a vital role in viral replication and serves as a fascinating therapeutic target. PF-07304814 is a covalent inhibitor targeting SARS-CoV-2 $ M^{pro} $ with favorable inhibition potency and drug-like properties, thus making it a promising drug candidate for the treatment of COVID-19. We previously solved the structure of PF-07304814 in complex with SARS-CoV-2 $ M^{pro} $. However, the binding modes of PF-07304814 with $ M^{pro} $s from evolving SARS-CoV-2 variants is under-determined. In the current study, we expressed six $ M^{pro} $ mutants (G15S, K90R, M49I, S46F, V186F, and Y54C) that have been identified in Omicron variants including the recently emerged XBB.1.16 subvariant and solved the crystal structures of PF-07304814 bound to $ M^{pro} $ mutants. Structural analysis provided insight into the key molecular determinants responsible for the interaction between PF-07304814 and these mutant $ M^{pro} $s. Patterns for PF-07304814 to bind with these investigated $ M^{pro} $ mutants and the wild-type $ M^{pro} $ are generally similar but with some differences as revealed by detailed structural comparison. Structural insights presented in this study will inform the development of novel drugs against SARS-CoV-2 and the possible conformation changes of $ M^{pro} $ mutants when bound to an inhibitor. SARS-CoV-2 (dpeaa)DE-He213 Variant (dpeaa)DE-He213 Main protease (dpeaa)DE-He213 Inhibitor (dpeaa)DE-He213 PF-07304814 (dpeaa)DE-He213 Zou, Xiaofang aut Zeng, Pei aut Zeng, Xiangyi aut Zhou, Xuelan aut Wang, Jie aut Zhang, Jin aut Li, Jian aut Enthalten in Molecular biomedicine Cham : Springer Nature Switzerland, 2020 4(2023), 1 vom: 03. Aug. (DE-627)1726726452 (DE-600)3033856-6 2662-8651 nnns volume:4 year:2023 number:1 day:03 month:08 https://dx.doi.org/10.1186/s43556-023-00134-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 4 2023 1 03 08
allfields_unstemmed	10.1186/s43556-023-00134-2 doi (DE-627)SPR052621839 (SPR)s43556-023-00134-2-e DE-627 ger DE-627 rakwb eng Jiang, Haihai verfasserin (orcid)0000-0002-1895-3040 aut Crystal structures of main protease ($ M^{pro} $) mutants of SARS-CoV-2 variants bound to PF-07304814 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract There is an urgent need to develop effective antiviral drugs to prevent the viral infection caused by constantly circulating SARS-CoV-2 as well as its variants. The main protease ($ M^{pro} $) of SARS-CoV-2 is a salient enzyme that plays a vital role in viral replication and serves as a fascinating therapeutic target. PF-07304814 is a covalent inhibitor targeting SARS-CoV-2 $ M^{pro} $ with favorable inhibition potency and drug-like properties, thus making it a promising drug candidate for the treatment of COVID-19. We previously solved the structure of PF-07304814 in complex with SARS-CoV-2 $ M^{pro} $. However, the binding modes of PF-07304814 with $ M^{pro} $s from evolving SARS-CoV-2 variants is under-determined. In the current study, we expressed six $ M^{pro} $ mutants (G15S, K90R, M49I, S46F, V186F, and Y54C) that have been identified in Omicron variants including the recently emerged XBB.1.16 subvariant and solved the crystal structures of PF-07304814 bound to $ M^{pro} $ mutants. Structural analysis provided insight into the key molecular determinants responsible for the interaction between PF-07304814 and these mutant $ M^{pro} $s. Patterns for PF-07304814 to bind with these investigated $ M^{pro} $ mutants and the wild-type $ M^{pro} $ are generally similar but with some differences as revealed by detailed structural comparison. Structural insights presented in this study will inform the development of novel drugs against SARS-CoV-2 and the possible conformation changes of $ M^{pro} $ mutants when bound to an inhibitor. SARS-CoV-2 (dpeaa)DE-He213 Variant (dpeaa)DE-He213 Main protease (dpeaa)DE-He213 Inhibitor (dpeaa)DE-He213 PF-07304814 (dpeaa)DE-He213 Zou, Xiaofang aut Zeng, Pei aut Zeng, Xiangyi aut Zhou, Xuelan aut Wang, Jie aut Zhang, Jin aut Li, Jian aut Enthalten in Molecular biomedicine Cham : Springer Nature Switzerland, 2020 4(2023), 1 vom: 03. Aug. (DE-627)1726726452 (DE-600)3033856-6 2662-8651 nnns volume:4 year:2023 number:1 day:03 month:08 https://dx.doi.org/10.1186/s43556-023-00134-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 4 2023 1 03 08
allfieldsGer	10.1186/s43556-023-00134-2 doi (DE-627)SPR052621839 (SPR)s43556-023-00134-2-e DE-627 ger DE-627 rakwb eng Jiang, Haihai verfasserin (orcid)0000-0002-1895-3040 aut Crystal structures of main protease ($ M^{pro} $) mutants of SARS-CoV-2 variants bound to PF-07304814 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract There is an urgent need to develop effective antiviral drugs to prevent the viral infection caused by constantly circulating SARS-CoV-2 as well as its variants. The main protease ($ M^{pro} $) of SARS-CoV-2 is a salient enzyme that plays a vital role in viral replication and serves as a fascinating therapeutic target. PF-07304814 is a covalent inhibitor targeting SARS-CoV-2 $ M^{pro} $ with favorable inhibition potency and drug-like properties, thus making it a promising drug candidate for the treatment of COVID-19. We previously solved the structure of PF-07304814 in complex with SARS-CoV-2 $ M^{pro} $. However, the binding modes of PF-07304814 with $ M^{pro} $s from evolving SARS-CoV-2 variants is under-determined. In the current study, we expressed six $ M^{pro} $ mutants (G15S, K90R, M49I, S46F, V186F, and Y54C) that have been identified in Omicron variants including the recently emerged XBB.1.16 subvariant and solved the crystal structures of PF-07304814 bound to $ M^{pro} $ mutants. Structural analysis provided insight into the key molecular determinants responsible for the interaction between PF-07304814 and these mutant $ M^{pro} $s. Patterns for PF-07304814 to bind with these investigated $ M^{pro} $ mutants and the wild-type $ M^{pro} $ are generally similar but with some differences as revealed by detailed structural comparison. Structural insights presented in this study will inform the development of novel drugs against SARS-CoV-2 and the possible conformation changes of $ M^{pro} $ mutants when bound to an inhibitor. SARS-CoV-2 (dpeaa)DE-He213 Variant (dpeaa)DE-He213 Main protease (dpeaa)DE-He213 Inhibitor (dpeaa)DE-He213 PF-07304814 (dpeaa)DE-He213 Zou, Xiaofang aut Zeng, Pei aut Zeng, Xiangyi aut Zhou, Xuelan aut Wang, Jie aut Zhang, Jin aut Li, Jian aut Enthalten in Molecular biomedicine Cham : Springer Nature Switzerland, 2020 4(2023), 1 vom: 03. Aug. (DE-627)1726726452 (DE-600)3033856-6 2662-8651 nnns volume:4 year:2023 number:1 day:03 month:08 https://dx.doi.org/10.1186/s43556-023-00134-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 4 2023 1 03 08
allfieldsSound	10.1186/s43556-023-00134-2 doi (DE-627)SPR052621839 (SPR)s43556-023-00134-2-e DE-627 ger DE-627 rakwb eng Jiang, Haihai verfasserin (orcid)0000-0002-1895-3040 aut Crystal structures of main protease ($ M^{pro} $) mutants of SARS-CoV-2 variants bound to PF-07304814 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract There is an urgent need to develop effective antiviral drugs to prevent the viral infection caused by constantly circulating SARS-CoV-2 as well as its variants. The main protease ($ M^{pro} $) of SARS-CoV-2 is a salient enzyme that plays a vital role in viral replication and serves as a fascinating therapeutic target. PF-07304814 is a covalent inhibitor targeting SARS-CoV-2 $ M^{pro} $ with favorable inhibition potency and drug-like properties, thus making it a promising drug candidate for the treatment of COVID-19. We previously solved the structure of PF-07304814 in complex with SARS-CoV-2 $ M^{pro} $. However, the binding modes of PF-07304814 with $ M^{pro} $s from evolving SARS-CoV-2 variants is under-determined. In the current study, we expressed six $ M^{pro} $ mutants (G15S, K90R, M49I, S46F, V186F, and Y54C) that have been identified in Omicron variants including the recently emerged XBB.1.16 subvariant and solved the crystal structures of PF-07304814 bound to $ M^{pro} $ mutants. Structural analysis provided insight into the key molecular determinants responsible for the interaction between PF-07304814 and these mutant $ M^{pro} $s. Patterns for PF-07304814 to bind with these investigated $ M^{pro} $ mutants and the wild-type $ M^{pro} $ are generally similar but with some differences as revealed by detailed structural comparison. Structural insights presented in this study will inform the development of novel drugs against SARS-CoV-2 and the possible conformation changes of $ M^{pro} $ mutants when bound to an inhibitor. SARS-CoV-2 (dpeaa)DE-He213 Variant (dpeaa)DE-He213 Main protease (dpeaa)DE-He213 Inhibitor (dpeaa)DE-He213 PF-07304814 (dpeaa)DE-He213 Zou, Xiaofang aut Zeng, Pei aut Zeng, Xiangyi aut Zhou, Xuelan aut Wang, Jie aut Zhang, Jin aut Li, Jian aut Enthalten in Molecular biomedicine Cham : Springer Nature Switzerland, 2020 4(2023), 1 vom: 03. Aug. (DE-627)1726726452 (DE-600)3033856-6 2662-8651 nnns volume:4 year:2023 number:1 day:03 month:08 https://dx.doi.org/10.1186/s43556-023-00134-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 4 2023 1 03 08
language	English
source	Enthalten in Molecular biomedicine 4(2023), 1 vom: 03. Aug. volume:4 year:2023 number:1 day:03 month:08
sourceStr	Enthalten in Molecular biomedicine 4(2023), 1 vom: 03. Aug. volume:4 year:2023 number:1 day:03 month:08
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authorswithroles_txt_mv	Jiang, Haihai @@aut@@ Zou, Xiaofang @@aut@@ Zeng, Pei @@aut@@ Zeng, Xiangyi @@aut@@ Zhou, Xuelan @@aut@@ Wang, Jie @@aut@@ Zhang, Jin @@aut@@ Li, Jian @@aut@@
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author	Jiang, Haihai
spellingShingle	Jiang, Haihai misc SARS-CoV-2 misc Variant misc Main protease misc Inhibitor misc PF-07304814 Crystal structures of main protease ($ M^{pro} $) mutants of SARS-CoV-2 variants bound to PF-07304814
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topic_title	Crystal structures of main protease ($ M^{pro} $) mutants of SARS-CoV-2 variants bound to PF-07304814 SARS-CoV-2 (dpeaa)DE-He213 Variant (dpeaa)DE-He213 Main protease (dpeaa)DE-He213 Inhibitor (dpeaa)DE-He213 PF-07304814 (dpeaa)DE-He213
topic	misc SARS-CoV-2 misc Variant misc Main protease misc Inhibitor misc PF-07304814
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title	Crystal structures of main protease ($ M^{pro} $) mutants of SARS-CoV-2 variants bound to PF-07304814
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title_full	Crystal structures of main protease ($ M^{pro} $) mutants of SARS-CoV-2 variants bound to PF-07304814
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author_browse	Jiang, Haihai Zou, Xiaofang Zeng, Pei Zeng, Xiangyi Zhou, Xuelan Wang, Jie Zhang, Jin Li, Jian
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title_sort	crystal structures of main protease ($ m^{pro} $) mutants of sars-cov-2 variants bound to pf-07304814
title_auth	Crystal structures of main protease ($ M^{pro} $) mutants of SARS-CoV-2 variants bound to PF-07304814
abstract	Abstract There is an urgent need to develop effective antiviral drugs to prevent the viral infection caused by constantly circulating SARS-CoV-2 as well as its variants. The main protease ($ M^{pro} $) of SARS-CoV-2 is a salient enzyme that plays a vital role in viral replication and serves as a fascinating therapeutic target. PF-07304814 is a covalent inhibitor targeting SARS-CoV-2 $ M^{pro} $ with favorable inhibition potency and drug-like properties, thus making it a promising drug candidate for the treatment of COVID-19. We previously solved the structure of PF-07304814 in complex with SARS-CoV-2 $ M^{pro} $. However, the binding modes of PF-07304814 with $ M^{pro} $s from evolving SARS-CoV-2 variants is under-determined. In the current study, we expressed six $ M^{pro} $ mutants (G15S, K90R, M49I, S46F, V186F, and Y54C) that have been identified in Omicron variants including the recently emerged XBB.1.16 subvariant and solved the crystal structures of PF-07304814 bound to $ M^{pro} $ mutants. Structural analysis provided insight into the key molecular determinants responsible for the interaction between PF-07304814 and these mutant $ M^{pro} $s. Patterns for PF-07304814 to bind with these investigated $ M^{pro} $ mutants and the wild-type $ M^{pro} $ are generally similar but with some differences as revealed by detailed structural comparison. Structural insights presented in this study will inform the development of novel drugs against SARS-CoV-2 and the possible conformation changes of $ M^{pro} $ mutants when bound to an inhibitor. © The Author(s) 2023
abstractGer	Abstract There is an urgent need to develop effective antiviral drugs to prevent the viral infection caused by constantly circulating SARS-CoV-2 as well as its variants. The main protease ($ M^{pro} $) of SARS-CoV-2 is a salient enzyme that plays a vital role in viral replication and serves as a fascinating therapeutic target. PF-07304814 is a covalent inhibitor targeting SARS-CoV-2 $ M^{pro} $ with favorable inhibition potency and drug-like properties, thus making it a promising drug candidate for the treatment of COVID-19. We previously solved the structure of PF-07304814 in complex with SARS-CoV-2 $ M^{pro} $. However, the binding modes of PF-07304814 with $ M^{pro} $s from evolving SARS-CoV-2 variants is under-determined. In the current study, we expressed six $ M^{pro} $ mutants (G15S, K90R, M49I, S46F, V186F, and Y54C) that have been identified in Omicron variants including the recently emerged XBB.1.16 subvariant and solved the crystal structures of PF-07304814 bound to $ M^{pro} $ mutants. Structural analysis provided insight into the key molecular determinants responsible for the interaction between PF-07304814 and these mutant $ M^{pro} $s. Patterns for PF-07304814 to bind with these investigated $ M^{pro} $ mutants and the wild-type $ M^{pro} $ are generally similar but with some differences as revealed by detailed structural comparison. Structural insights presented in this study will inform the development of novel drugs against SARS-CoV-2 and the possible conformation changes of $ M^{pro} $ mutants when bound to an inhibitor. © The Author(s) 2023
abstract_unstemmed	Abstract There is an urgent need to develop effective antiviral drugs to prevent the viral infection caused by constantly circulating SARS-CoV-2 as well as its variants. The main protease ($ M^{pro} $) of SARS-CoV-2 is a salient enzyme that plays a vital role in viral replication and serves as a fascinating therapeutic target. PF-07304814 is a covalent inhibitor targeting SARS-CoV-2 $ M^{pro} $ with favorable inhibition potency and drug-like properties, thus making it a promising drug candidate for the treatment of COVID-19. We previously solved the structure of PF-07304814 in complex with SARS-CoV-2 $ M^{pro} $. However, the binding modes of PF-07304814 with $ M^{pro} $s from evolving SARS-CoV-2 variants is under-determined. In the current study, we expressed six $ M^{pro} $ mutants (G15S, K90R, M49I, S46F, V186F, and Y54C) that have been identified in Omicron variants including the recently emerged XBB.1.16 subvariant and solved the crystal structures of PF-07304814 bound to $ M^{pro} $ mutants. Structural analysis provided insight into the key molecular determinants responsible for the interaction between PF-07304814 and these mutant $ M^{pro} $s. Patterns for PF-07304814 to bind with these investigated $ M^{pro} $ mutants and the wild-type $ M^{pro} $ are generally similar but with some differences as revealed by detailed structural comparison. Structural insights presented in this study will inform the development of novel drugs against SARS-CoV-2 and the possible conformation changes of $ M^{pro} $ mutants when bound to an inhibitor. © The Author(s) 2023
collection_details	GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700
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title_short	Crystal structures of main protease ($ M^{pro} $) mutants of SARS-CoV-2 variants bound to PF-07304814
url	https://dx.doi.org/10.1186/s43556-023-00134-2
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author2	Zou, Xiaofang Zeng, Pei Zeng, Xiangyi Zhou, Xuelan Wang, Jie Zhang, Jin Li, Jian
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up_date	2024-07-03T13:35:15.310Z
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The main protease ($ M^{pro} $) of SARS-CoV-2 is a salient enzyme that plays a vital role in viral replication and serves as a fascinating therapeutic target. PF-07304814 is a covalent inhibitor targeting SARS-CoV-2 $ M^{pro} $ with favorable inhibition potency and drug-like properties, thus making it a promising drug candidate for the treatment of COVID-19. We previously solved the structure of PF-07304814 in complex with SARS-CoV-2 $ M^{pro} $. However, the binding modes of PF-07304814 with $ M^{pro} $s from evolving SARS-CoV-2 variants is under-determined. In the current study, we expressed six $ M^{pro} $ mutants (G15S, K90R, M49I, S46F, V186F, and Y54C) that have been identified in Omicron variants including the recently emerged XBB.1.16 subvariant and solved the crystal structures of PF-07304814 bound to $ M^{pro} $ mutants. Structural analysis provided insight into the key molecular determinants responsible for the interaction between PF-07304814 and these mutant $ M^{pro} $s. Patterns for PF-07304814 to bind with these investigated $ M^{pro} $ mutants and the wild-type $ M^{pro} $ are generally similar but with some differences as revealed by detailed structural comparison. Structural insights presented in this study will inform the development of novel drugs against SARS-CoV-2 and the possible conformation changes of $ M^{pro} $ mutants when bound to an inhibitor.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">SARS-CoV-2</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Variant</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Main protease</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Inhibitor</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">PF-07304814</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Zou, Xiaofang</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Zeng, Pei</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Zeng, Xiangyi</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Zhou, Xuelan</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wang, Jie</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Zhang, Jin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Li, Jian</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">Molecular biomedicine</subfield><subfield code="d">Cham : Springer Nature Switzerland, 2020</subfield><subfield code="g">4(2023), 1 vom: 03. 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Crystal structures of main protease ($ M^{pro} $) mutants of SARS-CoV-2 variants bound to PF-07304814

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