Development of Broad‐Spectrum Halomethyl Ketone Inhibitors Against Coronavirus Main Protease 3CLpro
Identifieur interne : 003399 ( Main/Exploration ); précédent : 003398; suivant : 003400Development of Broad‐Spectrum Halomethyl Ketone Inhibitors Against Coronavirus Main Protease 3CLpro
Auteurs : Usman Bacha [États-Unis] ; Jennifer Barrila [États-Unis] ; Sandra B. Gabelli [États-Unis] ; Yoshiaki Kiso [Japon] ; L. Mario Amzel [États-Unis] ; Ernesto Freire [États-Unis]Source :
- Chemical Biology & Drug Design [ 1747-0277 ] ; 2008-07.
Descripteurs français
- KwdFr :
- Antiviraux (), Cinétique, Conception de médicament, Coronavirus (), Coronavirus (enzymologie), Cristallographie aux rayons X, Cysteine endopeptidases (), Cétones (antagonistes et inhibiteurs), Inhibiteurs de protéases (), Inhibiteurs de protéases (synthèse chimique), Protéines virales (), Protéines virales (antagonistes et inhibiteurs), Relation structure-activité.
- MESH :
- antagonistes et inhibiteurs : Cétones, Protéines virales.
- enzymologie : Coronavirus.
- synthèse chimique : Inhibiteurs de protéases.
- Antiviraux, Cinétique, Conception de médicament, Coronavirus, Cristallographie aux rayons X, Cysteine endopeptidases, Inhibiteurs de protéases, Protéines virales, Relation structure-activité.
English descriptors
- KwdEn :
- Antiviral Agents (chemistry), Coronavirus (drug effects), Coronavirus (enzymology), Crystallography, X-Ray, Cysteine Endopeptidases (chemistry), Drug Design, Ketones (antagonists & inhibitors), Kinetics, Protease Inhibitors (chemical synthesis), Protease Inhibitors (chemistry), Structure-Activity Relationship, Viral Proteins (antagonists & inhibitors), Viral Proteins (chemistry).
- MESH :
- chemical , antagonists & inhibitors : Ketones, Viral Proteins.
- chemical , chemical synthesis : Protease Inhibitors.
- chemical , chemistry : Antiviral Agents, Cysteine Endopeptidases, Protease Inhibitors, Viral Proteins.
- drug effects : Coronavirus.
- enzymology : Coronavirus.
- Crystallography, X-Ray, Drug Design, Kinetics, Structure-Activity Relationship.
Abstract
Coronaviruses comprise a large group of RNA viruses with diverse host specificity. The emergence of highly pathogenic strains like the SARS coronavirus (SARS‐CoV), and the discovery of two new coronaviruses, NL‐63 and HKU1, corroborates the high rate of mutation and recombination that have enabled them to cross species barriers and infect novel hosts. For that reason, the development of broad‐spectrum antivirals that are effective against several members of this family is highly desirable. This goal can be accomplished by designing inhibitors against a target, such as the main protease 3CLpro (Mpro), which is highly conserved among all coronaviruses. Here 3CLpro derived from the SARS‐CoV was used as the primary target to identify a new class of inhibitors containing a halomethyl ketone warhead. The compounds are highly potent against SARS 3CLpro with Ki’s as low as 300 nm. The crystal structure of the complex of one of the compounds with 3CLpro indicates that this inhibitor forms a thioether linkage between the halomethyl carbon of the warhead and the catalytic Cys 145. Furthermore, Structure Activity Relationship (SAR) studies of these compounds have led to the identification of a pharmacophore that accurately defines the essential molecular features required for the high affinity.
Url:
DOI: 10.1111/j.1747-0285.2008.00679.x
Affiliations:
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Gabelli</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biophysics and Biophysical Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Kiso, Yoshiaki" sort="Kiso, Yoshiaki" uniqKey="Kiso Y" first="Yoshiaki" last="Kiso">Yoshiaki Kiso</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina‐ku, Kyoto 607‐8412</wicri:regionArea><wicri:noRegion>Kyoto 607‐8412</wicri:noRegion></affiliation></author><author><name sortKey="Mario Amzel, L" sort="Mario Amzel, L" uniqKey="Mario Amzel L" first="L." last="Mario Amzel">L. Mario Amzel</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biophysics and Biophysical Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Freire, Ernesto" sort="Freire, Ernesto" uniqKey="Freire E" first="Ernesto" last="Freire">Ernesto Freire</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biology, The Johns Hopkins University, Baltimore, MD 21218</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation><affiliation wicri:level="1"><country wicri:rule="url">États-Unis</country></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Chemical Biology & Drug Design</title><title level="j" type="alt">CHEMICAL BIOLOGY DRUG DESIGN</title><idno type="ISSN">1747-0277</idno><idno type="eISSN">1747-0285</idno><imprint><biblScope unit="vol">72</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="34">34</biblScope><biblScope unit="page" to="49">49</biblScope><biblScope unit="page-count">16</biblScope><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="2008-07">2008-07</date></imprint><idno type="ISSN">1747-0277</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1747-0277</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral Agents (chemistry)</term><term>Coronavirus (drug effects)</term><term>Coronavirus (enzymology)</term><term>Crystallography, X-Ray</term><term>Cysteine Endopeptidases (chemistry)</term><term>Drug Design</term><term>Ketones (antagonists & inhibitors)</term><term>Kinetics</term><term>Protease Inhibitors (chemical synthesis)</term><term>Protease Inhibitors (chemistry)</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>Antiviraux ()</term><term>Cinétique</term><term>Conception de médicament</term><term>Coronavirus ()</term><term>Coronavirus (enzymologie)</term><term>Cristallographie aux rayons X</term><term>Cysteine endopeptidases ()</term><term>Cétones (antagonistes et inhibiteurs)</term><term>Inhibiteurs de protéases ()</term><term>Inhibiteurs de protéases (synthèse chimique)</term><term>Protéines virales ()</term><term>Protéines virales (antagonistes et inhibiteurs)</term><term>Relation structure-activité</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Ketones</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Protease Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term><term>Cysteine Endopeptidases</term><term>Protease Inhibitors</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Cétones</term><term>Protéines virales</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Coronavirus</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Coronavirus</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Coronavirus</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Inhibiteurs de protéases</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Crystallography, X-Ray</term><term>Drug Design</term><term>Kinetics</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Antiviraux</term><term>Cinétique</term><term>Conception de médicament</term><term>Coronavirus</term><term>Cristallographie aux rayons X</term><term>Cysteine endopeptidases</term><term>Inhibiteurs de protéases</term><term>Protéines virales</term><term>Relation structure-activité</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Coronaviruses comprise a large group of RNA viruses with diverse host specificity. The emergence of highly pathogenic strains like the SARS coronavirus (SARS‐CoV), and the discovery of two new coronaviruses, NL‐63 and HKU1, corroborates the high rate of mutation and recombination that have enabled them to cross species barriers and infect novel hosts. For that reason, the development of broad‐spectrum antivirals that are effective against several members of this family is highly desirable. This goal can be accomplished by designing inhibitors against a target, such as the main protease 3CLpro (Mpro), which is highly conserved among all coronaviruses. Here 3CLpro derived from the SARS‐CoV was used as the primary target to identify a new class of inhibitors containing a halomethyl ketone warhead. The compounds are highly potent against SARS 3CLpro with Ki’s as low as 300 nm. The crystal structure of the complex of one of the compounds with 3CLpro indicates that this inhibitor forms a thioether linkage between the halomethyl carbon of the warhead and the catalytic Cys 145. Furthermore, Structure Activity Relationship (SAR) studies of these compounds have led to the identification of a pharmacophore that accurately defines the essential molecular features required for the high affinity.</div></front></TEI><affiliations><list><country><li>Japon</li><li>États-Unis</li></country><region><li>Maryland</li></region></list><tree><country name="États-Unis"><region name="Maryland"><name sortKey="Bacha, Usman" sort="Bacha, Usman" uniqKey="Bacha U" first="Usman" last="Bacha">Usman Bacha</name></region><name sortKey="Barrila, Jennifer" sort="Barrila, Jennifer" uniqKey="Barrila J" first="Jennifer" last="Barrila">Jennifer Barrila</name><name sortKey="Freire, Ernesto" sort="Freire, Ernesto" uniqKey="Freire E" first="Ernesto" last="Freire">Ernesto Freire</name><name sortKey="Freire, Ernesto" sort="Freire, Ernesto" uniqKey="Freire E" first="Ernesto" last="Freire">Ernesto Freire</name><name sortKey="Gabelli, Sandra B" sort="Gabelli, Sandra B" uniqKey="Gabelli S" first="Sandra B." last="Gabelli">Sandra B. Gabelli</name><name sortKey="Mario Amzel, L" sort="Mario Amzel, L" uniqKey="Mario Amzel L" first="L." last="Mario Amzel">L. Mario Amzel</name></country><country name="Japon"><noRegion><name sortKey="Kiso, Yoshiaki" sort="Kiso, Yoshiaki" uniqKey="Kiso Y" first="Yoshiaki" last="Kiso">Yoshiaki Kiso</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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