SrasV1, Main, Merge, bibRecord, 003606

Heteroaromatic ester inhibitors of hepatitis A virus 3C proteinase : Evaluation of mode of action

Identifieur interne : 003606 ( Main/Merge ); précédent : 003605; suivant : 003607

Heteroaromatic ester inhibitors of hepatitis A virus 3C proteinase : Evaluation of mode of action

Auteurs : Carly Huitema [Canada] ; JIANMIN ZHANG [Canada] ; JIANG YIN [Canada] ; Michael N. G. James [Canada] ; John C. Vederas [Canada] ; Lindsay D. Eltis [Canada]

Source :

Bioorganic & medicinal chemistry [ 0968-0896 ] ; 2008.

RBID : Pascal:08-0382927

Descripteurs français

Pascal (Inist)
- Relation structure activité, Synthèse chimique, Virus hépatite A, Composé non peptide, Mécanisme action, Picornain 3C, Antiviral, Dérivé de la pyridine, Dérivé du furane, Modèle moléculaire, Complexe enzyme inhibiteur, Mode liaison, Modélisation, 2-Furoique acide ester 5-bromo-3-pyridyle.

English descriptors

KwdEn :
- Antiviral, Binding mode, Chemical synthesis, Furan derivatives, Hepatitis A virus, Inhibitor enzyme complex, Mechanism of action, Modeling, Molecular model, Non peptide compound, Picornain 3C, Pyridine derivatives, Structure activity relation.

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_icS of 120-240 nM. 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.

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Le document en format XML

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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral</term>
<term>Binding mode</term>
<term>Chemical synthesis</term>
<term>Furan derivatives</term>
<term>Hepatitis A virus</term>
<term>Inhibitor enzyme complex</term>
<term>Mechanism of action</term>
<term>Modeling</term>
<term>Molecular model</term>
<term>Non peptide compound</term>
<term>Picornain 3C</term>
<term>Pyridine derivatives</term>
<term>Structure activity relation</term>
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<keywords scheme="Pascal" xml:lang="fr"><term>Relation structure activité</term>
<term>Synthèse chimique</term>
<term>Virus hépatite A</term>
<term>Composé non peptide</term>
<term>Mécanisme action</term>
<term>Picornain 3C</term>
<term>Antiviral</term>
<term>Dérivé de la pyridine</term>
<term>Dérivé du furane</term>
<term>Modèle moléculaire</term>
<term>Complexe enzyme inhibiteur</term>
<term>Mode liaison</term>
<term>Modélisation</term>
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<front><div type="abstract" xml:lang="en">-The related 3C and 3C-like proteinase (3C<sup>pro</sup>
 and 3CL<sup>pro</sup>
) 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<sup>pro</sup>
. Three of the compounds, which also had furan rings, inhibited the cleavage activity of HAV 3C<sup>pro</sup>
 with K<sub>ic</sub>
S of 120-240 nM. HPLC-based assays revealed that the inhibitors were slowly hydrolyzed by both HAV 3C<sup>pro</sup>
 and SARS 3CL<sup>pro</sup>
, 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<sup>pro</sup>
.</div>
</front>
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<tree><country name="Canada"><noRegion><name sortKey="Huitema, Carly" sort="Huitema, Carly" uniqKey="Huitema C" first="Carly" last="Huitema">Carly Huitema</name>
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<name sortKey="Eltis, Lindsay D" sort="Eltis, Lindsay D" uniqKey="Eltis L" first="Lindsay D." last="Eltis">Lindsay D. Eltis</name>
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<name sortKey="Jiang Yin" sort="Jiang Yin" uniqKey="Jiang Yin" last="Jiang Yin">JIANG YIN</name>
<name sortKey="Jianmin Zhang" sort="Jianmin Zhang" uniqKey="Jianmin Zhang" last="Jianmin Zhang">JIANMIN ZHANG</name>
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Heteroaromatic ester inhibitors of hepatitis A virus 3C proteinase : Evaluation of mode of action

Heteroaromatic ester inhibitors of hepatitis A virus 3C proteinase : Evaluation of mode of action

Source :

Descripteurs français

English descriptors

Abstract

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