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X-ray structure and inhibition of the feline infectious peritonitis virus 3C-like protease: Structural implications for drug design
Feline infectious peritonitis (FIP) is a deadly disease that effects both domestic and wild cats and is caused by a mutation in feline coronavirus (FCoV) that allows the virus to replicate in macrophages. Currently, there are no treatments or vaccines available for the treatment of FIP even though i...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier Ltd.
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896745/ https://www.ncbi.nlm.nih.gov/pubmed/26592814 http://dx.doi.org/10.1016/j.bmcl.2015.10.023 |
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author | St. John, Sarah E. Therkelsen, Matthew D. Nyalapatla, Prasanth R. Osswald, Heather L. Ghosh, Arun K. Mesecar, Andrew D. |
author_facet | St. John, Sarah E. Therkelsen, Matthew D. Nyalapatla, Prasanth R. Osswald, Heather L. Ghosh, Arun K. Mesecar, Andrew D. |
author_sort | St. John, Sarah E. |
collection | PubMed |
description | Feline infectious peritonitis (FIP) is a deadly disease that effects both domestic and wild cats and is caused by a mutation in feline coronavirus (FCoV) that allows the virus to replicate in macrophages. Currently, there are no treatments or vaccines available for the treatment of FIP even though it kills approximately 5% of cats in multi-cat households per year. In an effort to develop small molecule drugs targeting FIP for the treatment of cats, we screened a small set of designed peptidomimetic inhibitors for inhibition of FIPV-3CL(pro), identifying two compounds with low to sub-micromolar inhibition, compound 6 (IC(50) = 0.59 ± 0.06 μM) and compound 7 (IC(50) = 1.3 ± 0.1 μM). We determined the first X-ray crystal structure of FIPV-3CL(pro) in complex with the best inhibitor identified, compound 6, to a resolution of 2.10 Å to better understand the structural basis for inhibitor specificity. Our study provides important insights into the structural requirements for the inhibition of FIPV-3CL(pro) by peptidomimetic inhibitors and expands the current structural knowledge of coronaviral 3CL(pro) architecture. |
format | Online Article Text |
id | pubmed-5896745 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Elsevier Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-58967452018-04-12 X-ray structure and inhibition of the feline infectious peritonitis virus 3C-like protease: Structural implications for drug design St. John, Sarah E. Therkelsen, Matthew D. Nyalapatla, Prasanth R. Osswald, Heather L. Ghosh, Arun K. Mesecar, Andrew D. Bioorg Med Chem Lett Article Feline infectious peritonitis (FIP) is a deadly disease that effects both domestic and wild cats and is caused by a mutation in feline coronavirus (FCoV) that allows the virus to replicate in macrophages. Currently, there are no treatments or vaccines available for the treatment of FIP even though it kills approximately 5% of cats in multi-cat households per year. In an effort to develop small molecule drugs targeting FIP for the treatment of cats, we screened a small set of designed peptidomimetic inhibitors for inhibition of FIPV-3CL(pro), identifying two compounds with low to sub-micromolar inhibition, compound 6 (IC(50) = 0.59 ± 0.06 μM) and compound 7 (IC(50) = 1.3 ± 0.1 μM). We determined the first X-ray crystal structure of FIPV-3CL(pro) in complex with the best inhibitor identified, compound 6, to a resolution of 2.10 Å to better understand the structural basis for inhibitor specificity. Our study provides important insights into the structural requirements for the inhibition of FIPV-3CL(pro) by peptidomimetic inhibitors and expands the current structural knowledge of coronaviral 3CL(pro) architecture. Elsevier Ltd. 2015-11-15 2015-10-13 /pmc/articles/PMC5896745/ /pubmed/26592814 http://dx.doi.org/10.1016/j.bmcl.2015.10.023 Text en Copyright © 2015 Elsevier Ltd. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |
spellingShingle | Article St. John, Sarah E. Therkelsen, Matthew D. Nyalapatla, Prasanth R. Osswald, Heather L. Ghosh, Arun K. Mesecar, Andrew D. X-ray structure and inhibition of the feline infectious peritonitis virus 3C-like protease: Structural implications for drug design |
title | X-ray structure and inhibition of the feline infectious peritonitis virus 3C-like protease: Structural implications for drug design |
title_full | X-ray structure and inhibition of the feline infectious peritonitis virus 3C-like protease: Structural implications for drug design |
title_fullStr | X-ray structure and inhibition of the feline infectious peritonitis virus 3C-like protease: Structural implications for drug design |
title_full_unstemmed | X-ray structure and inhibition of the feline infectious peritonitis virus 3C-like protease: Structural implications for drug design |
title_short | X-ray structure and inhibition of the feline infectious peritonitis virus 3C-like protease: Structural implications for drug design |
title_sort | x-ray structure and inhibition of the feline infectious peritonitis virus 3c-like protease: structural implications for drug design |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896745/ https://www.ncbi.nlm.nih.gov/pubmed/26592814 http://dx.doi.org/10.1016/j.bmcl.2015.10.023 |
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