Structural Basis for Inhibition of the SARS‐CoV‐2 nsp16 by Substrate‐Based Dual Site Inhibitors
Coronaviruses, including SARS‐CoV‐2, possess an mRNA 5′ capping apparatus capable of mimicking the natural eukaryotic capping signature. Two SAM‐dependent methylating enzymes play important roles in this process: nsp14 methylates the N7 of the guanosine cap, and nsp16‐nsp10 methylates the 2′‐O‐ of s...
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| Vydáno v: | ChemMedChem Ročník 19; číslo 24; s. e202400618 - n/a |
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16.12.2024
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| ISSN: | 1860-7179, 1860-7187, 1860-7187 |
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| Abstract | Coronaviruses, including SARS‐CoV‐2, possess an mRNA 5′ capping apparatus capable of mimicking the natural eukaryotic capping signature. Two SAM‐dependent methylating enzymes play important roles in this process: nsp14 methylates the N7 of the guanosine cap, and nsp16‐nsp10 methylates the 2′‐O‐ of subsequent nucleotides of viral mRNA. The 2′‐O‐methylation performed by nsp16‐nsp10 is crucial for the escape of the viral RNA from innate immunity. Inhibition of this enzymatic activity has been proposed as a way to combat coronaviruses. In this study, we employed X‐ray crystallography to analyze the binding of the SAM analogues to the active site of nsp16‐nsp10. We obtained eleven 3D crystal structures of the nsp16‐nsp10 complexes with SAM‐derived inhibitors, demonstrated different conformations of the methionine substituting part of the molecules, and confirmed that simultaneous dual‐site targeting of both SAM and RNA sites correlates with higher inhibitory potential.
Structural information on the binding of S‐adenosyl methionine (SAM) analogues to SARS‐CoV‐2 nsp16 shows that targeting both the SAM and RNA binding sites simultaneously enhances inhibitory potential. |
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| AbstractList | Coronaviruses, including SARS-CoV-2, possess an mRNA 5' capping apparatus capable of mimicking the natural eukaryotic capping signature. Two SAM-dependent methylating enzymes play important roles in this process: nsp14 methylates the N7 of the guanosine cap, and nsp16-nsp10 methylates the 2'-O- of subsequent nucleotides of viral mRNA. The 2'-O-methylation performed by nsp16-nsp10 is crucial for the escape of the viral RNA from innate immunity. Inhibition of this enzymatic activity has been proposed as a way to combat coronaviruses. In this study, we employed X-ray crystallography to analyze the binding of the SAM analogues to the active site of nsp16-nsp10. We obtained eleven 3D crystal structures of the nsp16-nsp10 complexes with SAM-derived inhibitors, demonstrated different conformations of the methionine substituting part of the molecules, and confirmed that simultaneous dual-site targeting of both SAM and RNA sites correlates with higher inhibitory potential.Coronaviruses, including SARS-CoV-2, possess an mRNA 5' capping apparatus capable of mimicking the natural eukaryotic capping signature. Two SAM-dependent methylating enzymes play important roles in this process: nsp14 methylates the N7 of the guanosine cap, and nsp16-nsp10 methylates the 2'-O- of subsequent nucleotides of viral mRNA. The 2'-O-methylation performed by nsp16-nsp10 is crucial for the escape of the viral RNA from innate immunity. Inhibition of this enzymatic activity has been proposed as a way to combat coronaviruses. In this study, we employed X-ray crystallography to analyze the binding of the SAM analogues to the active site of nsp16-nsp10. We obtained eleven 3D crystal structures of the nsp16-nsp10 complexes with SAM-derived inhibitors, demonstrated different conformations of the methionine substituting part of the molecules, and confirmed that simultaneous dual-site targeting of both SAM and RNA sites correlates with higher inhibitory potential. Coronaviruses, including SARS‐CoV‐2, possess an mRNA 5′ capping apparatus capable of mimicking the natural eukaryotic capping signature. Two SAM‐dependent methylating enzymes play important roles in this process: nsp14 methylates the N7 of the guanosine cap, and nsp16‐nsp10 methylates the 2′‐O‐ of subsequent nucleotides of viral mRNA. The 2′‐O‐methylation performed by nsp16‐nsp10 is crucial for the escape of the viral RNA from innate immunity. Inhibition of this enzymatic activity has been proposed as a way to combat coronaviruses. In this study, we employed X‐ray crystallography to analyze the binding of the SAM analogues to the active site of nsp16‐nsp10. We obtained eleven 3D crystal structures of the nsp16‐nsp10 complexes with SAM‐derived inhibitors, demonstrated different conformations of the methionine substituting part of the molecules, and confirmed that simultaneous dual‐site targeting of both SAM and RNA sites correlates with higher inhibitory potential. Structural information on the binding of S‐adenosyl methionine (SAM) analogues to SARS‐CoV‐2 nsp16 shows that targeting both the SAM and RNA binding sites simultaneously enhances inhibitory potential. Coronaviruses, including SARS‐CoV‐2, possess an mRNA 5′ capping apparatus capable of mimicking the natural eukaryotic capping signature. Two SAM‐dependent methylating enzymes play important roles in this process: nsp14 methylates the N7 of the guanosine cap, and nsp16‐nsp10 methylates the 2′‐O‐ of subsequent nucleotides of viral mRNA. The 2′‐O‐methylation performed by nsp16‐nsp10 is crucial for the escape of the viral RNA from innate immunity. Inhibition of this enzymatic activity has been proposed as a way to combat coronaviruses. In this study, we employed X‐ray crystallography to analyze the binding of the SAM analogues to the active site of nsp16‐nsp10. We obtained eleven 3D crystal structures of the nsp16‐nsp10 complexes with SAM‐derived inhibitors, demonstrated different conformations of the methionine substituting part of the molecules, and confirmed that simultaneous dual‐site targeting of both SAM and RNA sites correlates with higher inhibitory potential. Coronaviruses, including SARS‐CoV‐2, possess an mRNA 5′ capping apparatus capable of mimicking the natural eukaryotic capping signature. Two SAM‐dependent methylating enzymes play important roles in this process: nsp14 methylates the N7 of the guanosine cap, and nsp16‐nsp10 methylates the 2′‐O‐ of subsequent nucleotides of viral mRNA. The 2′‐O‐methylation performed by nsp16‐nsp10 is crucial for the escape of the viral RNA from innate immunity. Inhibition of this enzymatic activity has been proposed as a way to combat coronaviruses. In this study, we employed X‐ray crystallography to analyze the binding of the SAM analogues to the active site of nsp16‐nsp10. We obtained eleven 3D crystal structures of the nsp16‐nsp10 complexes with SAM‐derived inhibitors, demonstrated different conformations of the methionine substituting part of the molecules, and confirmed that simultaneous dual‐site targeting of both SAM and RNA sites correlates with higher inhibitory potential. Structural information on the binding of S‐adenosyl methionine (SAM) analogues to SARS‐CoV‐2 nsp16 shows that targeting both the SAM and RNA binding sites simultaneously enhances inhibitory potential. |
| Author | Rudusa, Laura Bula, Anna L. Tars, Kaspars Jaudzems, Kristaps Bobrovs, Raitis Jirgensons, Aigars Zelencova‐Gopejenko, Diana Kalnins, Gints Sisovs, Mihails Bobileva, Olga |
| AuthorAffiliation | 1 Latvian Biomedical Research and Study Centre Ratsupites 1 k-1 LV1067 Riga Latvia 2 Latvian Institute of Organic Synthesis Aizkraukles 21 Riga LV1006 Latvia 3 University of Latvia Jelgavas 1 LV1004 Riga Latvia |
| AuthorAffiliation_xml | – name: 2 Latvian Institute of Organic Synthesis Aizkraukles 21 Riga LV1006 Latvia – name: 1 Latvian Biomedical Research and Study Centre Ratsupites 1 k-1 LV1067 Riga Latvia – name: 3 University of Latvia Jelgavas 1 LV1004 Riga Latvia |
| Author_xml | – sequence: 1 givenname: Gints surname: Kalnins fullname: Kalnins, Gints organization: Latvian Biomedical Research and Study Centre – sequence: 2 givenname: Laura surname: Rudusa fullname: Rudusa, Laura organization: Latvian Institute of Organic Synthesis – sequence: 3 givenname: Anna L. surname: Bula fullname: Bula, Anna L. organization: Latvian Institute of Organic Synthesis – sequence: 4 givenname: Diana surname: Zelencova‐Gopejenko fullname: Zelencova‐Gopejenko, Diana organization: Latvian Institute of Organic Synthesis – sequence: 5 givenname: Olga surname: Bobileva fullname: Bobileva, Olga organization: Latvian Institute of Organic Synthesis – sequence: 6 givenname: Mihails surname: Sisovs fullname: Sisovs, Mihails organization: Latvian Biomedical Research and Study Centre – sequence: 7 givenname: Kaspars surname: Tars fullname: Tars, Kaspars organization: University of Latvia – sequence: 8 givenname: Aigars surname: Jirgensons fullname: Jirgensons, Aigars organization: Latvian Institute of Organic Synthesis – sequence: 9 givenname: Kristaps surname: Jaudzems fullname: Jaudzems, Kristaps organization: University of Latvia – sequence: 10 givenname: Raitis orcidid: 0000-0002-0221-8658 surname: Bobrovs fullname: Bobrovs, Raitis email: raitis.bobrovs@osi.lv organization: Latvian Institute of Organic Synthesis |
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| Keywords | Medicinal chemistry SARS-CoV-2 nsp16 Structural biology Methyltransferase |
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| Snippet | Coronaviruses, including SARS‐CoV‐2, possess an mRNA 5′ capping apparatus capable of mimicking the natural eukaryotic capping signature. Two SAM‐dependent... Coronaviruses, including SARS-CoV-2, possess an mRNA 5' capping apparatus capable of mimicking the natural eukaryotic capping signature. Two SAM-dependent... |
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| SubjectTerms | Antiviral Agents - chemistry Antiviral Agents - pharmacology Binding Sites Capping Catalytic Domain Coronaviruses COVID-19 Crystallography Crystallography, X-Ray Enzymatic activity Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Humans Inhibitors Innate immunity Medicinal chemistry Methionine Methylation Methyltransferase Methyltransferases - antagonists & inhibitors Methyltransferases - chemistry Methyltransferases - metabolism Models, Molecular mRNA mRNA guanylyltransferase nsp16 Nucleotides S-Adenosylmethionine - chemistry S-Adenosylmethionine - metabolism SARS-CoV-2 SARS-CoV-2 - drug effects SARS-CoV-2 - enzymology Severe acute respiratory syndrome Severe acute respiratory syndrome coronavirus 2 Structural biology Substrate inhibition Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - chemistry Viral Nonstructural Proteins - metabolism Viral Regulatory and Accessory Proteins |
| Title | Structural Basis for Inhibition of the SARS‐CoV‐2 nsp16 by Substrate‐Based Dual Site Inhibitors |
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