Design and synthesis of new tripeptide-type SARS-CoV 3CL protease inhibitors containing an electrophilic arylketone moiety.
Identifieur interne : 001967 ( Main/Exploration ); précédent : 001966; suivant : 001968Design and synthesis of new tripeptide-type SARS-CoV 3CL protease inhibitors containing an electrophilic arylketone moiety.
Auteurs : Sho Konno [Japon] ; Pillaiyar Thanigaimalai ; Takehito Yamamoto ; Kiyohiko Nakada ; Rie Kakiuchi ; Kentaro Takayama ; Yuri Yamazaki ; Fumika Yakushiji ; Kenichi Akaji ; Yoshiaki Kiso ; Yuko Kawasaki ; Shen-En Chen ; Ernesto Freire ; Yoshio HayashiSource :
- Bioorganic & medicinal chemistry [ 1464-3391 ] ; 2013.
Descripteurs français
- KwdFr :
- Benzothiazoles (), Conception de médicament, Cysteine endopeptidases (), Cysteine endopeptidases (métabolisme), Inhibiteurs de protéases (), Inhibiteurs de protéases (métabolisme), Inhibiteurs de protéases (synthèse chimique), Liaison aux protéines, Liaison hydrogène, Oligopeptides (), Oligopeptides (métabolisme), Oligopeptides (synthèse chimique), Protéines virales (antagonistes et inhibiteurs), Protéines virales (métabolisme), Relation structure-activité, Simulation de docking moléculaire, Sites de fixation, Structure tertiaire des protéines, Virus du SRAS (métabolisme).
- MESH :
- antagonistes et inhibiteurs : Protéines virales.
- métabolisme : Cysteine endopeptidases, Inhibiteurs de protéases, Oligopeptides, Protéines virales, Virus du SRAS.
- synthèse chimique : Inhibiteurs de protéases, Oligopeptides.
- Benzothiazoles, Conception de médicament, Cysteine endopeptidases, Inhibiteurs de protéases, Liaison aux protéines, Liaison hydrogène, Oligopeptides, Relation structure-activité, Simulation de docking moléculaire, Sites de fixation, Structure tertiaire des protéines.
English descriptors
- KwdEn :
- Benzothiazoles (chemistry), Binding Sites, Cysteine Endopeptidases (chemistry), Cysteine Endopeptidases (metabolism), Drug Design, Hydrogen Bonding, Molecular Docking Simulation, Oligopeptides (chemical synthesis), Oligopeptides (chemistry), Oligopeptides (metabolism), Protease Inhibitors (chemical synthesis), Protease Inhibitors (chemistry), Protease Inhibitors (metabolism), Protein Binding, Protein Structure, Tertiary, SARS Virus (metabolism), Structure-Activity Relationship, Viral Proteins (antagonists & inhibitors), Viral Proteins (metabolism).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemical synthesis : Oligopeptides, Protease Inhibitors.
- chemical , chemistry : Benzothiazoles, Cysteine Endopeptidases, Oligopeptides, Protease Inhibitors.
- chemical , metabolism : Cysteine Endopeptidases, Oligopeptides, Protease Inhibitors, Viral Proteins.
- metabolism : SARS Virus.
- Binding Sites, Drug Design, Hydrogen Bonding, Molecular Docking Simulation, Protein Binding, Protein Structure, Tertiary, Structure-Activity Relationship.
Abstract
We describe here the design, synthesis and biological evaluation of a series of molecules toward the development of novel peptidomimetic inhibitors of SARS-CoV 3CL(pro). A docking study involving binding between the initial lead compound 1 and the SARS-CoV 3CL(pro) motivated the replacement of a thiazole with a benzothiazole unit as a warhead moiety at the P1' site. This modification led to the identification of more potent derivatives, including 2i, 2k, 2m, 2o, and 2p, with IC(50) or K(i) values in the submicromolar to nanomolar range. In particular, compounds 2i and 2p exhibited the most potent inhibitory activities, with K(i) values of 4.1 and 3.1 nM, respectively. The peptidomimetic compounds identified through this process are attractive leads for the development of potential therapeutic agents against SARS. The structural requirements of the peptidomimetics with potent inhibitory activities against SARS-CoV 3CL(pro) may be summarized as follows: (i) the presence of a benzothiazole warhead at the S1'-position; (ii) hydrogen bonding capabilities at the cyclic lactam of the S1-site; (iii) appropriate stereochemistry and hydrophobic moiety size at the S2-site and (iv) a unique folding conformation assumed by the phenoxyacetyl moiety at the S4-site.
DOI: 10.1016/j.bmc.2012.11.017
PubMed: 23245752
Affiliations:
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Le document en format XML
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Konno</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Thanigaimalai, Pillaiyar" sort="Thanigaimalai, Pillaiyar" uniqKey="Thanigaimalai P" first="Pillaiyar" last="Thanigaimalai">Pillaiyar Thanigaimalai</name></author><author><name sortKey="Yamamoto, Takehito" sort="Yamamoto, Takehito" uniqKey="Yamamoto T" first="Takehito" last="Yamamoto">Takehito Yamamoto</name></author><author><name sortKey="Nakada, Kiyohiko" sort="Nakada, Kiyohiko" uniqKey="Nakada K" first="Kiyohiko" last="Nakada">Kiyohiko Nakada</name></author><author><name sortKey="Kakiuchi, Rie" sort="Kakiuchi, Rie" uniqKey="Kakiuchi R" first="Rie" last="Kakiuchi">Rie Kakiuchi</name></author><author><name sortKey="Takayama, Kentaro" sort="Takayama, Kentaro" uniqKey="Takayama K" first="Kentaro" last="Takayama">Kentaro Takayama</name></author><author><name sortKey="Yamazaki, Yuri" sort="Yamazaki, Yuri" uniqKey="Yamazaki Y" first="Yuri" last="Yamazaki">Yuri Yamazaki</name></author><author><name sortKey="Yakushiji, Fumika" sort="Yakushiji, Fumika" uniqKey="Yakushiji F" first="Fumika" last="Yakushiji">Fumika Yakushiji</name></author><author><name sortKey="Akaji, Kenichi" sort="Akaji, Kenichi" uniqKey="Akaji K" first="Kenichi" last="Akaji">Kenichi Akaji</name></author><author><name sortKey="Kiso, Yoshiaki" sort="Kiso, Yoshiaki" uniqKey="Kiso Y" first="Yoshiaki" last="Kiso">Yoshiaki Kiso</name></author><author><name sortKey="Kawasaki, Yuko" sort="Kawasaki, Yuko" uniqKey="Kawasaki Y" first="Yuko" last="Kawasaki">Yuko Kawasaki</name></author><author><name sortKey="Chen, Shen En" sort="Chen, Shen En" uniqKey="Chen S" first="Shen-En" last="Chen">Shen-En Chen</name></author><author><name sortKey="Freire, Ernesto" sort="Freire, Ernesto" uniqKey="Freire E" first="Ernesto" last="Freire">Ernesto Freire</name></author><author><name sortKey="Hayashi, Yoshio" sort="Hayashi, Yoshio" uniqKey="Hayashi Y" first="Yoshio" last="Hayashi">Yoshio Hayashi</name></author></analytic><series><title level="j">Bioorganic & medicinal chemistry</title><idno type="eISSN">1464-3391</idno><imprint><date when="2013" type="published">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Benzothiazoles (chemistry)</term><term>Binding Sites</term><term>Cysteine Endopeptidases (chemistry)</term><term>Cysteine Endopeptidases (metabolism)</term><term>Drug Design</term><term>Hydrogen Bonding</term><term>Molecular Docking Simulation</term><term>Oligopeptides (chemical synthesis)</term><term>Oligopeptides (chemistry)</term><term>Oligopeptides (metabolism)</term><term>Protease Inhibitors (chemical synthesis)</term><term>Protease Inhibitors (chemistry)</term><term>Protease Inhibitors (metabolism)</term><term>Protein Binding</term><term>Protein Structure, Tertiary</term><term>SARS Virus (metabolism)</term><term>Structure-Activity Relationship</term><term>Viral Proteins (antagonists & inhibitors)</term><term>Viral Proteins (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Benzothiazoles ()</term><term>Conception de médicament</term><term>Cysteine endopeptidases ()</term><term>Cysteine endopeptidases (métabolisme)</term><term>Inhibiteurs de protéases ()</term><term>Inhibiteurs de protéases (métabolisme)</term><term>Inhibiteurs de protéases (synthèse chimique)</term><term>Liaison aux protéines</term><term>Liaison hydrogène</term><term>Oligopeptides ()</term><term>Oligopeptides (métabolisme)</term><term>Oligopeptides (synthèse chimique)</term><term>Protéines virales (antagonistes et inhibiteurs)</term><term>Protéines virales (métabolisme)</term><term>Relation structure-activité</term><term>Simulation de docking moléculaire</term><term>Sites de fixation</term><term>Structure tertiaire des protéines</term><term>Virus du SRAS (métabolisme)</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>Oligopeptides</term><term>Protease Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Benzothiazoles</term><term>Cysteine Endopeptidases</term><term>Oligopeptides</term><term>Protease Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Oligopeptides</term><term>Protease Inhibitors</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines virales</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Cysteine endopeptidases</term><term>Inhibiteurs de protéases</term><term>Oligopeptides</term><term>Protéines virales</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Inhibiteurs de protéases</term><term>Oligopeptides</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Binding Sites</term><term>Drug Design</term><term>Hydrogen Bonding</term><term>Molecular Docking Simulation</term><term>Protein Binding</term><term>Protein Structure, Tertiary</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Benzothiazoles</term><term>Conception de médicament</term><term>Cysteine endopeptidases</term><term>Inhibiteurs de protéases</term><term>Liaison aux protéines</term><term>Liaison hydrogène</term><term>Oligopeptides</term><term>Relation structure-activité</term><term>Simulation de docking moléculaire</term><term>Sites de fixation</term><term>Structure tertiaire des protéines</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">We describe here the design, synthesis and biological evaluation of a series of molecules toward the development of novel peptidomimetic inhibitors of SARS-CoV 3CL(pro). A docking study involving binding between the initial lead compound 1 and the SARS-CoV 3CL(pro) motivated the replacement of a thiazole with a benzothiazole unit as a warhead moiety at the P1' site. This modification led to the identification of more potent derivatives, including 2i, 2k, 2m, 2o, and 2p, with IC(50) or K(i) values in the submicromolar to nanomolar range. In particular, compounds 2i and 2p exhibited the most potent inhibitory activities, with K(i) values of 4.1 and 3.1 nM, respectively. The peptidomimetic compounds identified through this process are attractive leads for the development of potential therapeutic agents against SARS. The structural requirements of the peptidomimetics with potent inhibitory activities against SARS-CoV 3CL(pro) may be summarized as follows: (i) the presence of a benzothiazole warhead at the S1'-position; (ii) hydrogen bonding capabilities at the cyclic lactam of the S1-site; (iii) appropriate stereochemistry and hydrophobic moiety size at the S2-site and (iv) a unique folding conformation assumed by the phenoxyacetyl moiety at the S4-site.</div></front></TEI><affiliations><list><country><li>Japon</li></country><region><li>Région de Kantō</li></region><settlement><li>Tokyo</li></settlement></list><tree><noCountry><name sortKey="Akaji, Kenichi" sort="Akaji, Kenichi" uniqKey="Akaji K" first="Kenichi" last="Akaji">Kenichi Akaji</name><name sortKey="Chen, Shen En" sort="Chen, Shen En" uniqKey="Chen S" first="Shen-En" last="Chen">Shen-En Chen</name><name sortKey="Freire, Ernesto" sort="Freire, Ernesto" uniqKey="Freire E" first="Ernesto" last="Freire">Ernesto Freire</name><name sortKey="Hayashi, Yoshio" sort="Hayashi, Yoshio" uniqKey="Hayashi Y" first="Yoshio" last="Hayashi">Yoshio Hayashi</name><name sortKey="Kakiuchi, Rie" sort="Kakiuchi, Rie" uniqKey="Kakiuchi R" first="Rie" last="Kakiuchi">Rie Kakiuchi</name><name sortKey="Kawasaki, Yuko" sort="Kawasaki, Yuko" uniqKey="Kawasaki Y" first="Yuko" last="Kawasaki">Yuko Kawasaki</name><name sortKey="Kiso, Yoshiaki" sort="Kiso, Yoshiaki" uniqKey="Kiso Y" first="Yoshiaki" last="Kiso">Yoshiaki Kiso</name><name sortKey="Nakada, Kiyohiko" sort="Nakada, Kiyohiko" uniqKey="Nakada K" first="Kiyohiko" last="Nakada">Kiyohiko Nakada</name><name sortKey="Takayama, Kentaro" sort="Takayama, Kentaro" uniqKey="Takayama K" first="Kentaro" last="Takayama">Kentaro Takayama</name><name sortKey="Thanigaimalai, Pillaiyar" sort="Thanigaimalai, Pillaiyar" uniqKey="Thanigaimalai P" first="Pillaiyar" last="Thanigaimalai">Pillaiyar Thanigaimalai</name><name sortKey="Yakushiji, Fumika" sort="Yakushiji, Fumika" uniqKey="Yakushiji F" first="Fumika" last="Yakushiji">Fumika Yakushiji</name><name sortKey="Yamamoto, Takehito" sort="Yamamoto, Takehito" uniqKey="Yamamoto T" first="Takehito" last="Yamamoto">Takehito Yamamoto</name><name sortKey="Yamazaki, Yuri" sort="Yamazaki, Yuri" uniqKey="Yamazaki Y" first="Yuri" last="Yamazaki">Yuri Yamazaki</name></noCountry><country name="Japon"><region name="Région de Kantō"><name sortKey="Konno, Sho" sort="Konno, Sho" uniqKey="Konno S" first="Sho" last="Konno">Sho Konno</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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