Heteroaromatic ester inhibitors of hepatitis A virus 3C proteinase: Evaluation of mode of action.
Identifieur interne : 003102 ( Main/Exploration ); précédent : 003101; suivant : 003103Heteroaromatic ester inhibitors of hepatitis A virus 3C proteinase: Evaluation of mode of action.
Auteurs : Carly Huitema [Canada] ; Jianmin Zhang ; Jiang Yin ; Michael N G. James ; John C. Vederas ; Lindsay D. EltisSource :
- Bioorganic & medicinal chemistry [ 1464-3391 ] ; 2008.
Descripteurs français
- KwdFr :
- Composés hétérocycliques (), Composés hétérocycliques (pharmacologie), Composés hétérocycliques (synthèse chimique), Cysteine endopeptidases (), Esters (), Esters (pharmacologie), Esters (synthèse chimique), Hydrocarbures aromatiques (), Hydrocarbures aromatiques (pharmacologie), Hydrocarbures aromatiques (synthèse chimique), Inhibiteurs de protéases (), Inhibiteurs de protéases (pharmacologie), Inhibiteurs de protéases (synthèse chimique), Modèles moléculaires, Protéines virales (), Protéines virales (antagonistes et inhibiteurs), Relation dose-effet des médicaments, Relation structure-activité, Structure moléculaire, Stéréoisomérie.
- MESH :
- antagonistes et inhibiteurs : Protéines virales.
- pharmacologie : Composés hétérocycliques, Esters, Hydrocarbures aromatiques, Inhibiteurs de protéases.
- synthèse chimique : Composés hétérocycliques, Esters, Hydrocarbures aromatiques, Inhibiteurs de protéases.
- Composés hétérocycliques, Cysteine endopeptidases, Esters, Hydrocarbures aromatiques, Inhibiteurs de protéases, Modèles moléculaires, Protéines virales, Relation dose-effet des médicaments, Relation structure-activité, Structure moléculaire, Stéréoisomérie.
English descriptors
- KwdEn :
- Cysteine Endopeptidases (chemistry), Dose-Response Relationship, Drug, Esters (chemical synthesis), Esters (chemistry), Esters (pharmacology), Heterocyclic Compounds (chemical synthesis), Heterocyclic Compounds (chemistry), Heterocyclic Compounds (pharmacology), Hydrocarbons, Aromatic (chemical synthesis), Hydrocarbons, Aromatic (chemistry), Hydrocarbons, Aromatic (pharmacology), Models, Molecular, Molecular Structure, Protease Inhibitors (chemical synthesis), Protease Inhibitors (chemistry), Protease Inhibitors (pharmacology), Stereoisomerism, Structure-Activity Relationship, Viral Proteins (antagonists & inhibitors), Viral Proteins (chemistry).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemical synthesis : Esters, Heterocyclic Compounds, Hydrocarbons, Aromatic, Protease Inhibitors.
- chemical , chemistry : Cysteine Endopeptidases, Esters, Heterocyclic Compounds, Hydrocarbons, Aromatic, Protease Inhibitors, Viral Proteins.
- chemical , pharmacology : Esters, Heterocyclic Compounds, Hydrocarbons, Aromatic, Protease Inhibitors.
- Dose-Response Relationship, Drug, Models, Molecular, Molecular Structure, Stereoisomerism, Structure-Activity Relationship.
Abstract
The related 3C and 3C-like proteinase (3C(pro) and 3CL(pro)) of picornaviruses and coronaviruses, respectively, are good drug targets. As part of an effort to generate broad-spectrum inhibitors of these enzymes, we screened a library of inhibitors based on a halopyridinyl ester from a previous study of the severe acute respiratory syndrome (SARS) 3CL proteinase against Hepatitis A virus (HAV) 3C(pro). Three of the compounds, which also had furan rings, inhibited the cleavage activity of HAV 3C(pro) with K(ic)s of 120-240nM. HPLC-based assays revealed that the inhibitors were slowly hydrolyzed by both HAV 3C(pro) and SARS 3CL(pro), confirming the identity of the expected products. Mass spectrometric analyses indicated that this hydrolysis proceeded via an acyl-enzyme intermediate. Modeling studies indicated that the halopyridinyl moiety of the inhibitor fits tightly into the S1-binding pocket, consistent with the lack of tolerance of the inhibitors to modification in this portion of the molecule. These compounds are among the most potent non-peptidic inhibitors reported to date against a 3C(pro).
DOI: 10.1016/j.bmc.2008.03.059
PubMed: 18407505
Affiliations:
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: 001B70
- to stream PubMed, to step Curation: 001B70
- to stream PubMed, to step Checkpoint: 001B22
- to stream Ncbi, to step Merge: 001C26
- to stream Ncbi, to step Curation: 001C26
- to stream Ncbi, to step Checkpoint: 001C26
- to stream Main, to step Merge: 003188
- to stream Main, to step Curation: 003102
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Heteroaromatic ester inhibitors of hepatitis A virus 3C proteinase: Evaluation of mode of action.</title><author><name sortKey="Huitema, Carly" sort="Huitema, Carly" uniqKey="Huitema C" first="Carly" last="Huitema">Carly Huitema</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology, University of British Columbia, 2350 Health Science Mall, Vancouver, British Columbia, Canada V6T 1Z3.</nlm:affiliation><country>Canada</country><wicri:regionArea>Department of Microbiology, University of British Columbia, 2350 Health Science Mall, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Zhang, Jianmin" sort="Zhang, Jianmin" uniqKey="Zhang J" first="Jianmin" last="Zhang">Jianmin Zhang</name></author><author><name sortKey="Yin, Jiang" sort="Yin, Jiang" uniqKey="Yin J" first="Jiang" last="Yin">Jiang Yin</name></author><author><name sortKey="James, Michael N G" sort="James, Michael N G" uniqKey="James M" first="Michael N G" last="James">Michael N G. James</name></author><author><name sortKey="Vederas, John C" sort="Vederas, John C" uniqKey="Vederas J" first="John C" last="Vederas">John C. Vederas</name></author><author><name sortKey="Eltis, Lindsay D" sort="Eltis, Lindsay D" uniqKey="Eltis L" first="Lindsay D" last="Eltis">Lindsay D. Eltis</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2008">2008</date><idno type="RBID">pubmed:18407505</idno><idno type="pmid">18407505</idno><idno type="doi">10.1016/j.bmc.2008.03.059</idno><idno type="wicri:Area/PubMed/Corpus">001B70</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001B70</idno><idno type="wicri:Area/PubMed/Curation">001B70</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001B70</idno><idno type="wicri:Area/PubMed/Checkpoint">001B22</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">001B22</idno><idno type="wicri:Area/Ncbi/Merge">001C26</idno><idno type="wicri:Area/Ncbi/Curation">001C26</idno><idno type="wicri:Area/Ncbi/Checkpoint">001C26</idno><idno type="wicri:Area/Main/Merge">003188</idno><idno type="wicri:Area/Main/Curation">003102</idno><idno type="wicri:Area/Main/Exploration">003102</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Heteroaromatic ester inhibitors of hepatitis A virus 3C proteinase: Evaluation of mode of action.</title><author><name sortKey="Huitema, Carly" sort="Huitema, Carly" uniqKey="Huitema C" first="Carly" last="Huitema">Carly Huitema</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology, University of British Columbia, 2350 Health Science Mall, Vancouver, British Columbia, Canada V6T 1Z3.</nlm:affiliation><country>Canada</country><wicri:regionArea>Department of Microbiology, University of British Columbia, 2350 Health Science Mall, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Zhang, Jianmin" sort="Zhang, Jianmin" uniqKey="Zhang J" first="Jianmin" last="Zhang">Jianmin Zhang</name></author><author><name sortKey="Yin, Jiang" sort="Yin, Jiang" uniqKey="Yin J" first="Jiang" last="Yin">Jiang Yin</name></author><author><name sortKey="James, Michael N G" sort="James, Michael N G" uniqKey="James M" first="Michael N G" last="James">Michael N G. James</name></author><author><name sortKey="Vederas, John C" sort="Vederas, John C" uniqKey="Vederas J" first="John C" last="Vederas">John C. Vederas</name></author><author><name sortKey="Eltis, Lindsay D" sort="Eltis, Lindsay D" uniqKey="Eltis L" first="Lindsay D" last="Eltis">Lindsay D. Eltis</name></author></analytic><series><title level="j">Bioorganic & medicinal chemistry</title><idno type="eISSN">1464-3391</idno><imprint><date when="2008" type="published">2008</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Cysteine Endopeptidases (chemistry)</term><term>Dose-Response Relationship, Drug</term><term>Esters (chemical synthesis)</term><term>Esters (chemistry)</term><term>Esters (pharmacology)</term><term>Heterocyclic Compounds (chemical synthesis)</term><term>Heterocyclic Compounds (chemistry)</term><term>Heterocyclic Compounds (pharmacology)</term><term>Hydrocarbons, Aromatic (chemical synthesis)</term><term>Hydrocarbons, Aromatic (chemistry)</term><term>Hydrocarbons, Aromatic (pharmacology)</term><term>Models, Molecular</term><term>Molecular Structure</term><term>Protease Inhibitors (chemical synthesis)</term><term>Protease Inhibitors (chemistry)</term><term>Protease Inhibitors (pharmacology)</term><term>Stereoisomerism</term><term>Structure-Activity Relationship</term><term>Viral Proteins (antagonists & inhibitors)</term><term>Viral Proteins (chemistry)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Composés hétérocycliques ()</term><term>Composés hétérocycliques (pharmacologie)</term><term>Composés hétérocycliques (synthèse chimique)</term><term>Cysteine endopeptidases ()</term><term>Esters ()</term><term>Esters (pharmacologie)</term><term>Esters (synthèse chimique)</term><term>Hydrocarbures aromatiques ()</term><term>Hydrocarbures aromatiques (pharmacologie)</term><term>Hydrocarbures aromatiques (synthèse chimique)</term><term>Inhibiteurs de protéases ()</term><term>Inhibiteurs de protéases (pharmacologie)</term><term>Inhibiteurs de protéases (synthèse chimique)</term><term>Modèles moléculaires</term><term>Protéines virales ()</term><term>Protéines virales (antagonistes et inhibiteurs)</term><term>Relation dose-effet des médicaments</term><term>Relation structure-activité</term><term>Structure moléculaire</term><term>Stéréoisomérie</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Esters</term><term>Heterocyclic Compounds</term><term>Hydrocarbons, Aromatic</term><term>Protease Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Esters</term><term>Heterocyclic Compounds</term><term>Hydrocarbons, Aromatic</term><term>Protease Inhibitors</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Esters</term><term>Heterocyclic Compounds</term><term>Hydrocarbons, Aromatic</term><term>Protease Inhibitors</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines virales</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Composés hétérocycliques</term><term>Esters</term><term>Hydrocarbures aromatiques</term><term>Inhibiteurs de protéases</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Composés hétérocycliques</term><term>Esters</term><term>Hydrocarbures aromatiques</term><term>Inhibiteurs de protéases</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Dose-Response Relationship, Drug</term><term>Models, Molecular</term><term>Molecular Structure</term><term>Stereoisomerism</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Composés hétérocycliques</term><term>Cysteine endopeptidases</term><term>Esters</term><term>Hydrocarbures aromatiques</term><term>Inhibiteurs de protéases</term><term>Modèles moléculaires</term><term>Protéines virales</term><term>Relation dose-effet des médicaments</term><term>Relation structure-activité</term><term>Structure moléculaire</term><term>Stéréoisomérie</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The related 3C and 3C-like proteinase (3C(pro) and 3CL(pro)) of picornaviruses and coronaviruses, respectively, are good drug targets. As part of an effort to generate broad-spectrum inhibitors of these enzymes, we screened a library of inhibitors based on a halopyridinyl ester from a previous study of the severe acute respiratory syndrome (SARS) 3CL proteinase against Hepatitis A virus (HAV) 3C(pro). Three of the compounds, which also had furan rings, inhibited the cleavage activity of HAV 3C(pro) with K(ic)s of 120-240nM. HPLC-based assays revealed that the inhibitors were slowly hydrolyzed by both HAV 3C(pro) and SARS 3CL(pro), confirming the identity of the expected products. Mass spectrometric analyses indicated that this hydrolysis proceeded via an acyl-enzyme intermediate. Modeling studies indicated that the halopyridinyl moiety of the inhibitor fits tightly into the S1-binding pocket, consistent with the lack of tolerance of the inhibitors to modification in this portion of the molecule. These compounds are among the most potent non-peptidic inhibitors reported to date against a 3C(pro).</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><noCountry><name sortKey="Eltis, Lindsay D" sort="Eltis, Lindsay D" uniqKey="Eltis L" first="Lindsay D" last="Eltis">Lindsay D. Eltis</name><name sortKey="James, Michael N G" sort="James, Michael N G" uniqKey="James M" first="Michael N G" last="James">Michael N G. James</name><name sortKey="Vederas, John C" sort="Vederas, John C" uniqKey="Vederas J" first="John C" last="Vederas">John C. Vederas</name><name sortKey="Yin, Jiang" sort="Yin, Jiang" uniqKey="Yin J" first="Jiang" last="Yin">Jiang Yin</name><name sortKey="Zhang, Jianmin" sort="Zhang, Jianmin" uniqKey="Zhang J" first="Jianmin" last="Zhang">Jianmin Zhang</name></noCountry><country name="Canada"><noRegion><name sortKey="Huitema, Carly" sort="Huitema, Carly" uniqKey="Huitema C" first="Carly" last="Huitema">Carly Huitema</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/SrasV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 003102 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 003102 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= SrasV1
|flux= Main
|étape= Exploration
|type= RBID
|clé= pubmed:18407505
|texte= Heteroaromatic ester inhibitors of hepatitis A virus 3C proteinase: Evaluation of mode of action.
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:18407505" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \
| NlmPubMed2Wicri -a SrasV1
| This area was generated with Dilib version V0.6.33. |  |