Inhibition of severe acute respiratory syndrome-associated coronavirus (SARSCoV) by calpain inhibitors and β-D-N4-hydroxycytidine
Identifieur interne : 005B13 ( Main/Exploration ); précédent : 005B12; suivant : 005B14Inhibition of severe acute respiratory syndrome-associated coronavirus (SARSCoV) by calpain inhibitors and β-D-N4-hydroxycytidine
Auteurs : Dale L. Barnard [États-Unis] ; Valerie D. Hubbard [États-Unis] ; Jared Burton [États-Unis] ; Donald F. Smee [États-Unis] ; John D. Morrey [États-Unis] ; Michael J. Otto [États-Unis] ; Robert W. Sidwell [États-Unis]Source :
- Antiviral chemistry & chemotherapy [ 0956-3202 ] ; 2004.
Descripteurs français
- KwdFr :
- Animaux, Cellules Vero, Cytidine (analogues et dérivés), Cytidine (pharmacologie), Glycoprotéines (), Glycoprotéines (pharmacologie), Nucléosides (), Nucléosides (pharmacologie), Réplication virale (), Structure moléculaire, Syndrome respiratoire aigu sévère (virologie), Virus du SRAS (), Virus du SRAS (physiologie).
- MESH :
- analogues et dérivés : Cytidine.
- pharmacologie : Cytidine, Glycoprotéines, Nucléosides.
- physiologie : Virus du SRAS.
- virologie : Syndrome respiratoire aigu sévère.
- Pascal (Inist)
- Animaux, Antiviral, Cellules Vero, Glycoprotéines, In vitro, Coronavirus, Inhibiteur enzyme, Calpain, Cytidine, Guanosine, Adénosine, Analogue nucléoside, Nucléosides, Relation structure activité, Recherche développement, Réplication virale, Structure moléculaire, Syndrome respiratoire aigu sévère, Virus du SRAS.
English descriptors
- KwdEn :
- Adenosine, Animals, Antiviral, Calpain, Chlorocebus aethiops, Coronavirus, Cytidine, Cytidine (analogs & derivatives), Cytidine (pharmacology), Enzyme inhibitor, Glycoproteins (chemistry), Glycoproteins (pharmacology), Guanosine, In vitro, Molecular Structure, Nucleoside analog, Nucleosides (chemistry), Nucleosides (pharmacology), Research and development, SARS Virus (classification), SARS Virus (drug effects), SARS Virus (physiology), Severe Acute Respiratory Syndrome (virology), Severe acute respiratory syndrome, Structure activity relation, Vero Cells, Virus Replication (drug effects).
- MESH :
- chemical , analogs & derivatives : Cytidine.
- chemical , chemistry : Glycoproteins, Nucleosides.
- chemical , pharmacology : Cytidine, Glycoproteins, Nucleosides.
- classification : SARS Virus.
- drug effects : SARS Virus, Virus Replication.
- physiology : SARS Virus.
- virology : Severe Acute Respiratory Syndrome.
- Animals, Chlorocebus aethiops, Molecular Structure, Vero Cells.
Abstract
We evaluated two types of compounds for efficacy in inhibiting SARSCoV replication in vitro: calpain inhibitors (a class of cellular cysteine proteinases) and a number of nucleoside analogues. Cytopathic effect reduction assays visually determined with spectrophotometric verification by neutral red (NR) uptake assay were used to evaluate cytotoxicity and antiviral potency of the compounds. Significantly inhibitory compounds were then evaluated in virus yield reduction assays. Two calpain inhibitors, Val-Leu-CHO (calpain inhibitor VI) and Z-Val-Phe-Ala-CHO (calpain inhibitor III), were the most potent inhibitors of SARSCoV. By virus yield reduction assay, calpain inhibitor VI had a 90% effective concentration (EC90) of 3 μM and calpain inhibitor III had an EC90 of 15 μM. β-D-N4-hydroxycytidine was the most selective nucleoside analogue inhibitor with an EC90 of 6 μM by virus yield reduction assay. These compounds or analogues warrant further evaluation as potential therapies for treating SARS or could be used as lead compounds for discovery of more potent SARSCoV inhibitors.
Affiliations:
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Barnard</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University</s1><s2>Logan, UT</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author><author><name sortKey="Hubbard, Valerie D" sort="Hubbard, Valerie D" uniqKey="Hubbard V" first="Valerie D." last="Hubbard">Valerie D. Hubbard</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University</s1><s2>Logan, UT</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author><author><name sortKey="Burton, Jared" sort="Burton, Jared" uniqKey="Burton J" first="Jared" last="Burton">Jared Burton</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University</s1><s2>Logan, UT</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author><author><name sortKey="Smee, Donald F" sort="Smee, Donald F" uniqKey="Smee D" first="Donald F." last="Smee">Donald F. Smee</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University</s1><s2>Logan, UT</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author><author><name sortKey="Morrey, John D" sort="Morrey, John D" uniqKey="Morrey J" first="John D." last="Morrey">John D. Morrey</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University</s1><s2>Logan, UT</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author><author><name sortKey="Otto, Michael J" sort="Otto, Michael J" uniqKey="Otto M" first="Michael J." last="Otto">Michael J. Otto</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Pharmasset, Inc.</s1><s2>Tucker, Ga.</s2><s3>USA</s3><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Tucker, Ga.</wicri:noRegion></affiliation></author><author><name sortKey="Sidwell, Robert W" sort="Sidwell, Robert W" uniqKey="Sidwell R" first="Robert W." last="Sidwell">Robert W. Sidwell</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University</s1><s2>Logan, UT</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author></analytic><series><title level="j" type="main">Antiviral chemistry & chemotherapy</title><title level="j" type="abbreviated">Antivir. chem. chemother.</title><idno type="ISSN">0956-3202</idno><imprint><date when="2004">2004</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Antiviral chemistry & chemotherapy</title><title level="j" type="abbreviated">Antivir. chem. chemother.</title><idno type="ISSN">0956-3202</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adenosine</term><term>Animals</term><term>Antiviral</term><term>Calpain</term><term>Chlorocebus aethiops</term><term>Coronavirus</term><term>Cytidine</term><term>Cytidine (analogs & derivatives)</term><term>Cytidine (pharmacology)</term><term>Enzyme inhibitor</term><term>Glycoproteins (chemistry)</term><term>Glycoproteins (pharmacology)</term><term>Guanosine</term><term>In vitro</term><term>Molecular Structure</term><term>Nucleoside analog</term><term>Nucleosides (chemistry)</term><term>Nucleosides (pharmacology)</term><term>Research and development</term><term>SARS Virus (classification)</term><term>SARS Virus (drug effects)</term><term>SARS Virus (physiology)</term><term>Severe Acute Respiratory Syndrome (virology)</term><term>Severe acute respiratory syndrome</term><term>Structure activity relation</term><term>Vero Cells</term><term>Virus Replication (drug effects)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Cellules Vero</term><term>Cytidine (analogues et dérivés)</term><term>Cytidine (pharmacologie)</term><term>Glycoprotéines ()</term><term>Glycoprotéines (pharmacologie)</term><term>Nucléosides ()</term><term>Nucléosides (pharmacologie)</term><term>Réplication virale ()</term><term>Structure moléculaire</term><term>Syndrome respiratoire aigu sévère (virologie)</term><term>Virus du SRAS ()</term><term>Virus du SRAS (physiologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Cytidine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Glycoproteins</term><term>Nucleosides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Cytidine</term><term>Glycoproteins</term><term>Nucleosides</term></keywords><keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>Cytidine</term></keywords><keywords scheme="MESH" qualifier="classification" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>SARS Virus</term><term>Virus Replication</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Cytidine</term><term>Glycoprotéines</term><term>Nucléosides</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Chlorocebus aethiops</term><term>Molecular Structure</term><term>Vero Cells</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Animaux</term><term>Antiviral</term><term>Cellules Vero</term><term>Glycoprotéines</term><term>In vitro</term><term>Coronavirus</term><term>Inhibiteur enzyme</term><term>Calpain</term><term>Cytidine</term><term>Guanosine</term><term>Adénosine</term><term>Analogue nucléoside</term><term>Nucléosides</term><term>Relation structure activité</term><term>Recherche développement</term><term>Réplication virale</term><term>Structure moléculaire</term><term>Syndrome respiratoire aigu sévère</term><term>Virus du SRAS</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">We evaluated two types of compounds for efficacy in inhibiting SARSCoV replication in vitro: calpain inhibitors (a class of cellular cysteine proteinases) and a number of nucleoside analogues. Cytopathic effect reduction assays visually determined with spectrophotometric verification by neutral red (NR) uptake assay were used to evaluate cytotoxicity and antiviral potency of the compounds. Significantly inhibitory compounds were then evaluated in virus yield reduction assays. Two calpain inhibitors, Val-Leu-CHO (calpain inhibitor VI) and Z-Val-Phe-Ala-CHO (calpain inhibitor III), were the most potent inhibitors of SARSCoV. By virus yield reduction assay, calpain inhibitor VI had a 90% effective concentration (EC<sub>90</sub>) of 3 μM and calpain inhibitor III had an EC<sub>90</sub> of 15 μM. β-D-N<sup>4</sup>-hydroxycytidine was the most selective nucleoside analogue inhibitor with an EC<sub>90</sub> of 6 μM by virus yield reduction assay. These compounds or analogues warrant further evaluation as potential therapies for treating SARS or could be used as lead compounds for discovery of more potent SARSCoV inhibitors.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Utah</li></region></list><tree><country name="États-Unis"><region name="Utah"><name sortKey="Barnard, Dale L" sort="Barnard, Dale L" uniqKey="Barnard D" first="Dale L." last="Barnard">Dale L. Barnard</name></region><name sortKey="Burton, Jared" sort="Burton, Jared" uniqKey="Burton J" first="Jared" last="Burton">Jared Burton</name><name sortKey="Hubbard, Valerie D" sort="Hubbard, Valerie D" uniqKey="Hubbard V" first="Valerie D." last="Hubbard">Valerie D. Hubbard</name><name sortKey="Morrey, John D" sort="Morrey, John D" uniqKey="Morrey J" first="John D." last="Morrey">John D. Morrey</name><name sortKey="Otto, Michael J" sort="Otto, Michael J" uniqKey="Otto M" first="Michael J." last="Otto">Michael J. Otto</name><name sortKey="Sidwell, Robert W" sort="Sidwell, Robert W" uniqKey="Sidwell R" first="Robert W." last="Sidwell">Robert W. Sidwell</name><name sortKey="Smee, Donald F" sort="Smee, Donald F" uniqKey="Smee D" first="Donald F." last="Smee">Donald F. Smee</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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