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Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses
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| Zeitschriftentitel: | Journal of Virology |
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| Personen und Körperschaften: | , , , , , , , |
| In: | Journal of Virology, 86, 2012, 21, S. 11754-11762 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society for Microbiology
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| Schlagwörter: |
| author_facet |
Kim, Yunjeong Lovell, Scott Tiew, Kok-Chuan Mandadapu, Sivakoteswara Rao Alliston, Kevin R. Battaile, Kevin P. Groutas, William C. Chang, Kyeong-Ok Kim, Yunjeong Lovell, Scott Tiew, Kok-Chuan Mandadapu, Sivakoteswara Rao Alliston, Kevin R. Battaile, Kevin P. Groutas, William C. Chang, Kyeong-Ok |
|---|---|
| author |
Kim, Yunjeong Lovell, Scott Tiew, Kok-Chuan Mandadapu, Sivakoteswara Rao Alliston, Kevin R. Battaile, Kevin P. Groutas, William C. Chang, Kyeong-Ok |
| spellingShingle |
Kim, Yunjeong Lovell, Scott Tiew, Kok-Chuan Mandadapu, Sivakoteswara Rao Alliston, Kevin R. Battaile, Kevin P. Groutas, William C. Chang, Kyeong-Ok Journal of Virology Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses Virology Insect Science Immunology Microbiology |
| author_sort |
kim, yunjeong |
| spelling |
Kim, Yunjeong Lovell, Scott Tiew, Kok-Chuan Mandadapu, Sivakoteswara Rao Alliston, Kevin R. Battaile, Kevin P. Groutas, William C. Chang, Kyeong-Ok 0022-538X 1098-5514 American Society for Microbiology Virology Insect Science Immunology Microbiology http://dx.doi.org/10.1128/jvi.01348-12 <jats:title>ABSTRACT</jats:title> <jats:p> Phylogenetic analysis has demonstrated that some positive-sense RNA viruses can be classified into the picornavirus-like supercluster, which includes picornaviruses, caliciviruses, and coronaviruses. These viruses possess 3C or 3C-like proteases (3Cpro or 3CLpro, respectively), which contain a typical chymotrypsin-like fold and a catalytic triad (or dyad) with a Cys residue as a nucleophile. The conserved key sites of 3Cpro or 3CLpro may serve as attractive targets for the design of broad-spectrum antivirals for multiple viruses in the supercluster. We previously reported the structure-based design and synthesis of potent protease inhibitors of Norwalk virus (NV), a member of the <jats:named-content content-type="genus-species">Caliciviridae</jats:named-content> family. We report herein the broad-spectrum antiviral activities of three compounds possessing a common dipeptidyl residue with different warheads, i.e., an aldehyde (GC373), a bisulfite adduct (GC376), and an α-ketoamide (GC375), against viruses that belong to the supercluster. All compounds were highly effective against the majority of tested viruses, with half-maximal inhibitory concentrations in the high nanomolar or low micromolar range in enzyme- and/or cell-based assays and with high therapeutic indices. We also report the high-resolution X-ray cocrystal structures of NV 3CLpro-, poliovirus 3Cpro-, and transmissible gastroenteritis virus 3CLpro- GC376 inhibitor complexes, which show the compound covalently bound to a nucleophilic Cys residue in the catalytic site of the corresponding protease. We conclude that these compounds have the potential to be developed as antiviral therapeutics aimed at a single virus or multiple viruses in the picornavirus-like supercluster by targeting 3Cpro or 3CLpro. </jats:p> Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses Journal of Virology |
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American Society for Microbiology, 2012 |
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| title |
Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses |
| title_unstemmed |
Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses |
| title_full |
Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses |
| title_fullStr |
Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses |
| title_full_unstemmed |
Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses |
| title_short |
Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses |
| title_sort |
broad-spectrum antivirals against 3c or 3c-like proteases of picornaviruses, noroviruses, and coronaviruses |
| topic |
Virology Insect Science Immunology Microbiology |
| url |
http://dx.doi.org/10.1128/jvi.01348-12 |
| publishDate |
2012 |
| physical |
11754-11762 |
| description |
<jats:title>ABSTRACT</jats:title>
<jats:p>
Phylogenetic analysis has demonstrated that some positive-sense RNA viruses can be classified into the picornavirus-like supercluster, which includes picornaviruses, caliciviruses, and coronaviruses. These viruses possess 3C or 3C-like proteases (3Cpro or 3CLpro, respectively), which contain a typical chymotrypsin-like fold and a catalytic triad (or dyad) with a Cys residue as a nucleophile. The conserved key sites of 3Cpro or 3CLpro may serve as attractive targets for the design of broad-spectrum antivirals for multiple viruses in the supercluster. We previously reported the structure-based design and synthesis of potent protease inhibitors of Norwalk virus (NV), a member of the
<jats:named-content content-type="genus-species">Caliciviridae</jats:named-content>
family. We report herein the broad-spectrum antiviral activities of three compounds possessing a common dipeptidyl residue with different warheads, i.e., an aldehyde (GC373), a bisulfite adduct (GC376), and an α-ketoamide (GC375), against viruses that belong to the supercluster. All compounds were highly effective against the majority of tested viruses, with half-maximal inhibitory concentrations in the high nanomolar or low micromolar range in enzyme- and/or cell-based assays and with high therapeutic indices. We also report the high-resolution X-ray cocrystal structures of NV 3CLpro-, poliovirus 3Cpro-, and transmissible gastroenteritis virus 3CLpro- GC376 inhibitor complexes, which show the compound covalently bound to a nucleophilic Cys residue in the catalytic site of the corresponding protease. We conclude that these compounds have the potential to be developed as antiviral therapeutics aimed at a single virus or multiple viruses in the picornavirus-like supercluster by targeting 3Cpro or 3CLpro.
</jats:p> |
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| author | Kim, Yunjeong, Lovell, Scott, Tiew, Kok-Chuan, Mandadapu, Sivakoteswara Rao, Alliston, Kevin R., Battaile, Kevin P., Groutas, William C., Chang, Kyeong-Ok |
| author_facet | Kim, Yunjeong, Lovell, Scott, Tiew, Kok-Chuan, Mandadapu, Sivakoteswara Rao, Alliston, Kevin R., Battaile, Kevin P., Groutas, William C., Chang, Kyeong-Ok, Kim, Yunjeong, Lovell, Scott, Tiew, Kok-Chuan, Mandadapu, Sivakoteswara Rao, Alliston, Kevin R., Battaile, Kevin P., Groutas, William C., Chang, Kyeong-Ok |
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| description | <jats:title>ABSTRACT</jats:title> <jats:p> Phylogenetic analysis has demonstrated that some positive-sense RNA viruses can be classified into the picornavirus-like supercluster, which includes picornaviruses, caliciviruses, and coronaviruses. These viruses possess 3C or 3C-like proteases (3Cpro or 3CLpro, respectively), which contain a typical chymotrypsin-like fold and a catalytic triad (or dyad) with a Cys residue as a nucleophile. The conserved key sites of 3Cpro or 3CLpro may serve as attractive targets for the design of broad-spectrum antivirals for multiple viruses in the supercluster. We previously reported the structure-based design and synthesis of potent protease inhibitors of Norwalk virus (NV), a member of the <jats:named-content content-type="genus-species">Caliciviridae</jats:named-content> family. We report herein the broad-spectrum antiviral activities of three compounds possessing a common dipeptidyl residue with different warheads, i.e., an aldehyde (GC373), a bisulfite adduct (GC376), and an α-ketoamide (GC375), against viruses that belong to the supercluster. All compounds were highly effective against the majority of tested viruses, with half-maximal inhibitory concentrations in the high nanomolar or low micromolar range in enzyme- and/or cell-based assays and with high therapeutic indices. We also report the high-resolution X-ray cocrystal structures of NV 3CLpro-, poliovirus 3Cpro-, and transmissible gastroenteritis virus 3CLpro- GC376 inhibitor complexes, which show the compound covalently bound to a nucleophilic Cys residue in the catalytic site of the corresponding protease. We conclude that these compounds have the potential to be developed as antiviral therapeutics aimed at a single virus or multiple viruses in the picornavirus-like supercluster by targeting 3Cpro or 3CLpro. </jats:p> |
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| spelling | Kim, Yunjeong Lovell, Scott Tiew, Kok-Chuan Mandadapu, Sivakoteswara Rao Alliston, Kevin R. Battaile, Kevin P. Groutas, William C. Chang, Kyeong-Ok 0022-538X 1098-5514 American Society for Microbiology Virology Insect Science Immunology Microbiology http://dx.doi.org/10.1128/jvi.01348-12 <jats:title>ABSTRACT</jats:title> <jats:p> Phylogenetic analysis has demonstrated that some positive-sense RNA viruses can be classified into the picornavirus-like supercluster, which includes picornaviruses, caliciviruses, and coronaviruses. These viruses possess 3C or 3C-like proteases (3Cpro or 3CLpro, respectively), which contain a typical chymotrypsin-like fold and a catalytic triad (or dyad) with a Cys residue as a nucleophile. The conserved key sites of 3Cpro or 3CLpro may serve as attractive targets for the design of broad-spectrum antivirals for multiple viruses in the supercluster. We previously reported the structure-based design and synthesis of potent protease inhibitors of Norwalk virus (NV), a member of the <jats:named-content content-type="genus-species">Caliciviridae</jats:named-content> family. We report herein the broad-spectrum antiviral activities of three compounds possessing a common dipeptidyl residue with different warheads, i.e., an aldehyde (GC373), a bisulfite adduct (GC376), and an α-ketoamide (GC375), against viruses that belong to the supercluster. All compounds were highly effective against the majority of tested viruses, with half-maximal inhibitory concentrations in the high nanomolar or low micromolar range in enzyme- and/or cell-based assays and with high therapeutic indices. We also report the high-resolution X-ray cocrystal structures of NV 3CLpro-, poliovirus 3Cpro-, and transmissible gastroenteritis virus 3CLpro- GC376 inhibitor complexes, which show the compound covalently bound to a nucleophilic Cys residue in the catalytic site of the corresponding protease. We conclude that these compounds have the potential to be developed as antiviral therapeutics aimed at a single virus or multiple viruses in the picornavirus-like supercluster by targeting 3Cpro or 3CLpro. </jats:p> Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses Journal of Virology |
| spellingShingle | Kim, Yunjeong, Lovell, Scott, Tiew, Kok-Chuan, Mandadapu, Sivakoteswara Rao, Alliston, Kevin R., Battaile, Kevin P., Groutas, William C., Chang, Kyeong-Ok, Journal of Virology, Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses, Virology, Insect Science, Immunology, Microbiology |
| title | Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses |
| title_full | Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses |
| title_fullStr | Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses |
| title_full_unstemmed | Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses |
| title_short | Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses |
| title_sort | broad-spectrum antivirals against 3c or 3c-like proteases of picornaviruses, noroviruses, and coronaviruses |
| title_unstemmed | Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses |
| topic | Virology, Insect Science, Immunology, Microbiology |
| url | http://dx.doi.org/10.1128/jvi.01348-12 |