Identification of a broad-spectrum antiviral small molecule against severe acute respiratory syndrome coronavirus and Ebola, Hendra, and Nipah viruses by using a novel high-throughput screening assay.
Identifieur interne : 001634 ( Main/Exploration ); précédent : 001633; suivant : 001635Identification of a broad-spectrum antiviral small molecule against severe acute respiratory syndrome coronavirus and Ebola, Hendra, and Nipah viruses by using a novel high-throughput screening assay.
Auteurs : Hatem A. Elshabrawy [États-Unis] ; Jilao Fan ; Christine S. Haddad ; Kiira Ratia ; Christopher C. Broder ; Michael Caffrey ; Bellur S. PrabhakarSource :
- Journal of virology [ 1098-5514 ] ; 2014.
Descripteurs français
- KwdFr :
- Antiviraux (pharmacologie), Bibliothèques de petites molécules (pharmacologie), Cathepsine L (métabolisme), Ebolavirus (), Ebolavirus (métabolisme), Humains, Maladies virales (enzymologie), Maladies virales (virologie), Protéines de l'enveloppe virale (métabolisme), Tests de criblage à haut débit (), Virus Hendra (), Virus Hendra (métabolisme), Virus Nipah (), Virus Nipah (métabolisme), Virus du SRAS (), Virus du SRAS (métabolisme), Évaluation préclinique de médicament ().
- MESH :
- enzymologie : Maladies virales.
- métabolisme : Cathepsine L, Ebolavirus, Protéines de l'enveloppe virale, Virus Hendra, Virus Nipah, Virus du SRAS.
- pharmacologie : Antiviraux, Bibliothèques de petites molécules.
- virologie : Maladies virales.
- Ebolavirus, Humains, Tests de criblage à haut débit, Virus Hendra, Virus Nipah, Virus du SRAS, Évaluation préclinique de médicament.
English descriptors
- KwdEn :
- Antiviral Agents (pharmacology), Cathepsin L (metabolism), Drug Evaluation, Preclinical (methods), Ebolavirus (drug effects), Ebolavirus (metabolism), Hendra Virus (drug effects), Hendra Virus (metabolism), High-Throughput Screening Assays (methods), Humans, Nipah Virus (drug effects), Nipah Virus (metabolism), SARS Virus (drug effects), SARS Virus (metabolism), Small Molecule Libraries (pharmacology), Viral Envelope Proteins (metabolism), Virus Diseases (enzymology), Virus Diseases (virology).
- MESH :
- chemical , metabolism : Cathepsin L, Viral Envelope Proteins.
- chemical , pharmacology : Antiviral Agents, Small Molecule Libraries.
- drug effects : Ebolavirus, Hendra Virus, Nipah Virus, SARS Virus.
- enzymology : Virus Diseases.
- metabolism : Ebolavirus, Hendra Virus, Nipah Virus, SARS Virus.
- methods : Drug Evaluation, Preclinical, High-Throughput Screening Assays.
- virology : Virus Diseases.
- Humans.
Abstract
Severe acute respiratory syndrome coronavirus (SARS-CoV) and Ebola, Hendra, and Nipah viruses are members of different viral families and are known causative agents of fatal viral diseases. These viruses depend on cathepsin L for entry into their target cells. The viral glycoproteins need to be primed by protease cleavage, rendering them active for fusion with the host cell membrane. In this study, we developed a novel high-throughput screening assay based on peptides, derived from the glycoproteins of the aforementioned viruses, which contain the cathepsin L cleavage site. We screened a library of 5,000 small molecules and discovered a small molecule that can inhibit the cathepsin L cleavage of all viral peptides with minimal inhibition of cleavage of a host protein-derived peptide (pro-neuropeptide Y). The small molecule inhibited the entry of all pseudotyped viruses in vitro and the cleavage of SARS-CoV spike glycoprotein in an in vitro cleavage assay. In addition, the Hendra and Nipah virus fusion glycoproteins were not cleaved in the presence of the small molecule in a cell-based cleavage assay. Furthermore, we demonstrate that the small molecule is a mixed inhibitor of cathepsin L. Our broad-spectrum antiviral small molecule appears to be an ideal candidate for future optimization and development into a potent antiviral against SARS-CoV and Ebola, Hendra, and Nipah viruses.
DOI: 10.1128/JVI.03050-13
PubMed: 24501399
Affiliations:
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Haddad</name></author><author><name sortKey="Ratia, Kiira" sort="Ratia, Kiira" uniqKey="Ratia K" first="Kiira" last="Ratia">Kiira Ratia</name></author><author><name sortKey="Broder, Christopher C" sort="Broder, Christopher C" uniqKey="Broder C" first="Christopher C" last="Broder">Christopher C. Broder</name></author><author><name sortKey="Caffrey, Michael" sort="Caffrey, Michael" uniqKey="Caffrey M" first="Michael" last="Caffrey">Michael Caffrey</name></author><author><name sortKey="Prabhakar, Bellur S" sort="Prabhakar, Bellur S" uniqKey="Prabhakar B" first="Bellur S" last="Prabhakar">Bellur S. 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These viruses depend on cathepsin L for entry into their target cells. The viral glycoproteins need to be primed by protease cleavage, rendering them active for fusion with the host cell membrane. In this study, we developed a novel high-throughput screening assay based on peptides, derived from the glycoproteins of the aforementioned viruses, which contain the cathepsin L cleavage site. We screened a library of 5,000 small molecules and discovered a small molecule that can inhibit the cathepsin L cleavage of all viral peptides with minimal inhibition of cleavage of a host protein-derived peptide (pro-neuropeptide Y). The small molecule inhibited the entry of all pseudotyped viruses in vitro and the cleavage of SARS-CoV spike glycoprotein in an in vitro cleavage assay. In addition, the Hendra and Nipah virus fusion glycoproteins were not cleaved in the presence of the small molecule in a cell-based cleavage assay. Furthermore, we demonstrate that the small molecule is a mixed inhibitor of cathepsin L. Our broad-spectrum antiviral small molecule appears to be an ideal candidate for future optimization and development into a potent antiviral against SARS-CoV and Ebola, Hendra, and Nipah viruses.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Illinois</li></region><settlement><li>Chicago</li></settlement><orgName><li>Université de l'Illinois à Chicago</li></orgName></list><tree><noCountry><name sortKey="Broder, Christopher C" sort="Broder, Christopher C" uniqKey="Broder C" first="Christopher C" last="Broder">Christopher C. Broder</name><name sortKey="Caffrey, Michael" sort="Caffrey, Michael" uniqKey="Caffrey M" first="Michael" last="Caffrey">Michael Caffrey</name><name sortKey="Fan, Jilao" sort="Fan, Jilao" uniqKey="Fan J" first="Jilao" last="Fan">Jilao Fan</name><name sortKey="Haddad, Christine S" sort="Haddad, Christine S" uniqKey="Haddad C" first="Christine S" last="Haddad">Christine S. Haddad</name><name sortKey="Prabhakar, Bellur S" sort="Prabhakar, Bellur S" uniqKey="Prabhakar B" first="Bellur S" last="Prabhakar">Bellur S. Prabhakar</name><name sortKey="Ratia, Kiira" sort="Ratia, Kiira" uniqKey="Ratia K" first="Kiira" last="Ratia">Kiira Ratia</name></noCountry><country name="États-Unis"><region name="Illinois"><name sortKey="Elshabrawy, Hatem A" sort="Elshabrawy, Hatem A" uniqKey="Elshabrawy H" first="Hatem A" last="Elshabrawy">Hatem A. Elshabrawy</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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