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Broad-Spectrum Allosteric Inhibition of Herpesvirus Proteases
[Image: see text] Herpesviruses rely on a homodimeric protease for viral capsid maturation. A small molecule, DD2, previously shown to disrupt dimerization of Kaposi’s sarcoma-associated herpesvirus protease (KSHV Pr) by trapping an inactive monomeric conformation and two analogues generated through...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American
Chemical Society
2014
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4108181/ https://www.ncbi.nlm.nih.gov/pubmed/24977643 http://dx.doi.org/10.1021/bi5003234 |
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author | Gable, Jonathan E. Lee, Gregory M. Jaishankar, Priyadarshini Hearn, Brian R. Waddling, Christopher A. Renslo, Adam R. Craik, Charles S. |
author_facet | Gable, Jonathan E. Lee, Gregory M. Jaishankar, Priyadarshini Hearn, Brian R. Waddling, Christopher A. Renslo, Adam R. Craik, Charles S. |
author_sort | Gable, Jonathan E. |
collection | PubMed |
description | [Image: see text] Herpesviruses rely on a homodimeric protease for viral capsid maturation. A small molecule, DD2, previously shown to disrupt dimerization of Kaposi’s sarcoma-associated herpesvirus protease (KSHV Pr) by trapping an inactive monomeric conformation and two analogues generated through carboxylate bioisosteric replacement (compounds 2 and 3) were shown to inhibit the associated proteases of all three human herpesvirus (HHV) subfamilies (α, β, and γ). Inhibition data reveal that compound 2 has potency comparable to or better than that of DD2 against the tested proteases. Nuclear magnetic resonance spectroscopy and a new application of the kinetic analysis developed by Zhang and Poorman [Zhang, Z. Y., Poorman, R. A., et al. (1991) J. Biol. Chem. 266, 15591–15594] show DD2, compound 2, and compound 3 inhibit HHV proteases by dimer disruption. All three compounds bind the dimer interface of other HHV proteases in a manner analogous to binding of DD2 to KSHV protease. The determination and analysis of cocrystal structures of both analogues with the KSHV Pr monomer verify and elaborate on the mode of binding for this chemical scaffold, explaining a newly observed critical structure–activity relationship. These results reveal a prototypical chemical scaffold for broad-spectrum allosteric inhibition of human herpesvirus proteases and an approach for the identification of small molecules that allosterically regulate protein activity by targeting protein–protein interactions. |
format | Online Article Text |
id | pubmed-4108181 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American
Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-41081812015-06-30 Broad-Spectrum Allosteric Inhibition of Herpesvirus Proteases Gable, Jonathan E. Lee, Gregory M. Jaishankar, Priyadarshini Hearn, Brian R. Waddling, Christopher A. Renslo, Adam R. Craik, Charles S. Biochemistry [Image: see text] Herpesviruses rely on a homodimeric protease for viral capsid maturation. A small molecule, DD2, previously shown to disrupt dimerization of Kaposi’s sarcoma-associated herpesvirus protease (KSHV Pr) by trapping an inactive monomeric conformation and two analogues generated through carboxylate bioisosteric replacement (compounds 2 and 3) were shown to inhibit the associated proteases of all three human herpesvirus (HHV) subfamilies (α, β, and γ). Inhibition data reveal that compound 2 has potency comparable to or better than that of DD2 against the tested proteases. Nuclear magnetic resonance spectroscopy and a new application of the kinetic analysis developed by Zhang and Poorman [Zhang, Z. Y., Poorman, R. A., et al. (1991) J. Biol. Chem. 266, 15591–15594] show DD2, compound 2, and compound 3 inhibit HHV proteases by dimer disruption. All three compounds bind the dimer interface of other HHV proteases in a manner analogous to binding of DD2 to KSHV protease. The determination and analysis of cocrystal structures of both analogues with the KSHV Pr monomer verify and elaborate on the mode of binding for this chemical scaffold, explaining a newly observed critical structure–activity relationship. These results reveal a prototypical chemical scaffold for broad-spectrum allosteric inhibition of human herpesvirus proteases and an approach for the identification of small molecules that allosterically regulate protein activity by targeting protein–protein interactions. American Chemical Society 2014-06-30 2014-07-22 /pmc/articles/PMC4108181/ /pubmed/24977643 http://dx.doi.org/10.1021/bi5003234 Text en Copyright © 2014 American Chemical Society Terms of Use (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) |
spellingShingle | Gable, Jonathan E. Lee, Gregory M. Jaishankar, Priyadarshini Hearn, Brian R. Waddling, Christopher A. Renslo, Adam R. Craik, Charles S. Broad-Spectrum Allosteric Inhibition of Herpesvirus Proteases |
title | Broad-Spectrum Allosteric Inhibition of Herpesvirus
Proteases |
title_full | Broad-Spectrum Allosteric Inhibition of Herpesvirus
Proteases |
title_fullStr | Broad-Spectrum Allosteric Inhibition of Herpesvirus
Proteases |
title_full_unstemmed | Broad-Spectrum Allosteric Inhibition of Herpesvirus
Proteases |
title_short | Broad-Spectrum Allosteric Inhibition of Herpesvirus
Proteases |
title_sort | broad-spectrum allosteric inhibition of herpesvirus
proteases |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4108181/ https://www.ncbi.nlm.nih.gov/pubmed/24977643 http://dx.doi.org/10.1021/bi5003234 |
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