Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases.
Identifieur interne : 001C44 ( Main/Exploration ); précédent : 001C43; suivant : 001C45Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases.
Auteurs : Ji-Young Park [Corée du Sud] ; Jang Hoon Kim ; Young Min Kim ; Hyung Jae Jeong ; Dae Wook Kim ; Ki Hun Park ; Hyung-Jun Kwon ; Su-Jin Park ; Woo Song Lee ; Young Bae RyuSource :
- Bioorganic & medicinal chemistry [ 1464-3391 ] ; 2012.
Descripteurs français
- KwdFr :
- Cinétique, Humains, Inhibiteurs de la cystéine protéinase (), Inhibiteurs de la cystéine protéinase (isolement et purification), Inhibiteurs de la cystéine protéinase (pharmacologie), Liaison aux protéines, Salvia miltiorrhiza (), Syndrome respiratoire aigu sévère (enzymologie), Syndrome respiratoire aigu sévère (traitement médicamenteux), Ubiquitinylation (), Virus du SRAS (), Virus du SRAS (enzymologie).
- MESH :
- enzymologie : Syndrome respiratoire aigu sévère, Virus du SRAS.
- isolement et purification : Inhibiteurs de la cystéine protéinase.
- pharmacologie : Inhibiteurs de la cystéine protéinase.
- traitement médicamenteux : Syndrome respiratoire aigu sévère.
- Cinétique, Humains, Inhibiteurs de la cystéine protéinase, Liaison aux protéines, Salvia miltiorrhiza, Ubiquitinylation, Virus du SRAS.
English descriptors
- KwdEn :
- Abietanes (chemistry), Abietanes (isolation & purification), Abietanes (pharmacology), Cysteine Proteinase Inhibitors (chemistry), Cysteine Proteinase Inhibitors (isolation & purification), Cysteine Proteinase Inhibitors (pharmacology), Humans, Kinetics, Protein Binding, SARS Virus (drug effects), SARS Virus (enzymology), Salvia miltiorrhiza (chemistry), Severe Acute Respiratory Syndrome (drug therapy), Severe Acute Respiratory Syndrome (enzymology), Ubiquitination (drug effects).
- MESH :
- chemical , chemistry : Abietanes, Cysteine Proteinase Inhibitors.
- chemical , isolation & purification : Abietanes, Cysteine Proteinase Inhibitors.
- chemical , pharmacology : Abietanes, Cysteine Proteinase Inhibitors.
- chemistry : Salvia miltiorrhiza.
- drug effects : SARS Virus, Ubiquitination.
- drug therapy : Severe Acute Respiratory Syndrome.
- enzymology : SARS Virus, Severe Acute Respiratory Syndrome.
- Humans, Kinetics, Protein Binding.
Abstract
In the search for anti-SARS-CoV, tanshinones derived from Salvia miltiorrhiza were found to be specific and selective inhibitors for the SARS-CoV 3CL(pro) and PL(pro), viral cysteine proteases. A literature search for studies involving the seven isolated tanshinone hits showed that at present, none have been identified as coronaviral protease inhibitors. We have identified that all of the isolated tanshinones are good inhibitors of both cysteine proteases. However, their activity was slightly affected by subtle changes in structure and targeting enzymes. All isolated compounds (1-7) act as time dependent inhibitors of PL(pro), but no improved inhibition was observed following preincubation with the 3CL(pro). In a detail kinetic mechanism study, all of the tanshinones except rosmariquinone (7) were identified as noncompetitive enzyme isomerization inhibitors. However, rosmariquinone (7) showed a different kinetic mechanism through mixed-type simple reversible slow-binding inhibition. Furthermore, tanshinone I (5) exhibited the most potent nanomolar level inhibitory activity toward deubiquitinating (IC(50)=0.7 μM). Additionally, the inhibition is selective because these compounds do not exert significant inhibitory effects against other proteases including chymotrysin, papain, and HIV protease. These findings provide potential inhibitors for SARS-CoV viral infection and replication.
DOI: 10.1016/j.bmc.2012.07.038
PubMed: 22884354
Affiliations:
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Le document en format XML
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last="Kim">Young Min Kim</name></author><author><name sortKey="Jeong, Hyung Jae" sort="Jeong, Hyung Jae" uniqKey="Jeong H" first="Hyung Jae" last="Jeong">Hyung Jae Jeong</name></author><author><name sortKey="Kim, Dae Wook" sort="Kim, Dae Wook" uniqKey="Kim D" first="Dae Wook" last="Kim">Dae Wook Kim</name></author><author><name sortKey="Park, Ki Hun" sort="Park, Ki Hun" uniqKey="Park K" first="Ki Hun" last="Park">Ki Hun Park</name></author><author><name sortKey="Kwon, Hyung Jun" sort="Kwon, Hyung Jun" uniqKey="Kwon H" first="Hyung-Jun" last="Kwon">Hyung-Jun Kwon</name></author><author><name sortKey="Park, Su Jin" sort="Park, Su Jin" uniqKey="Park S" first="Su-Jin" last="Park">Su-Jin Park</name></author><author><name sortKey="Lee, Woo Song" sort="Lee, Woo Song" uniqKey="Lee W" first="Woo Song" last="Lee">Woo Song Lee</name></author><author><name sortKey="Ryu, Young Bae" sort="Ryu, Young Bae" uniqKey="Ryu Y" first="Young Bae" last="Ryu">Young Bae 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Young Min" uniqKey="Kim Y" first="Young Min" last="Kim">Young Min Kim</name></author><author><name sortKey="Jeong, Hyung Jae" sort="Jeong, Hyung Jae" uniqKey="Jeong H" first="Hyung Jae" last="Jeong">Hyung Jae Jeong</name></author><author><name sortKey="Kim, Dae Wook" sort="Kim, Dae Wook" uniqKey="Kim D" first="Dae Wook" last="Kim">Dae Wook Kim</name></author><author><name sortKey="Park, Ki Hun" sort="Park, Ki Hun" uniqKey="Park K" first="Ki Hun" last="Park">Ki Hun Park</name></author><author><name sortKey="Kwon, Hyung Jun" sort="Kwon, Hyung Jun" uniqKey="Kwon H" first="Hyung-Jun" last="Kwon">Hyung-Jun Kwon</name></author><author><name sortKey="Park, Su Jin" sort="Park, Su Jin" uniqKey="Park S" first="Su-Jin" last="Park">Su-Jin Park</name></author><author><name sortKey="Lee, Woo Song" sort="Lee, Woo Song" uniqKey="Lee W" first="Woo Song" last="Lee">Woo Song Lee</name></author><author><name sortKey="Ryu, Young Bae" sort="Ryu, Young Bae" uniqKey="Ryu Y" first="Young Bae" last="Ryu">Young Bae Ryu</name></author></analytic><series><title level="j">Bioorganic & medicinal chemistry</title><idno type="eISSN">1464-3391</idno><imprint><date when="2012" type="published">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Abietanes (chemistry)</term><term>Abietanes (isolation & purification)</term><term>Abietanes (pharmacology)</term><term>Cysteine Proteinase Inhibitors (chemistry)</term><term>Cysteine Proteinase Inhibitors (isolation & purification)</term><term>Cysteine Proteinase Inhibitors (pharmacology)</term><term>Humans</term><term>Kinetics</term><term>Protein Binding</term><term>SARS Virus (drug effects)</term><term>SARS Virus (enzymology)</term><term>Salvia miltiorrhiza (chemistry)</term><term>Severe Acute Respiratory Syndrome (drug therapy)</term><term>Severe Acute Respiratory Syndrome (enzymology)</term><term>Ubiquitination (drug effects)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Cinétique</term><term>Humains</term><term>Inhibiteurs de la cystéine protéinase ()</term><term>Inhibiteurs de la cystéine protéinase (isolement et purification)</term><term>Inhibiteurs de la cystéine protéinase (pharmacologie)</term><term>Liaison aux protéines</term><term>Salvia miltiorrhiza ()</term><term>Syndrome respiratoire aigu sévère (enzymologie)</term><term>Syndrome respiratoire aigu sévère (traitement médicamenteux)</term><term>Ubiquitinylation ()</term><term>Virus du SRAS ()</term><term>Virus du SRAS (enzymologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Abietanes</term><term>Cysteine Proteinase Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="isolation & purification" xml:lang="en"><term>Abietanes</term><term>Cysteine Proteinase Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Abietanes</term><term>Cysteine Proteinase Inhibitors</term></keywords><keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>Salvia miltiorrhiza</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>SARS Virus</term><term>Ubiquitination</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>SARS Virus</term><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="isolement et purification" xml:lang="fr"><term>Inhibiteurs de la cystéine protéinase</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Inhibiteurs de la cystéine protéinase</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Humans</term><term>Kinetics</term><term>Protein Binding</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Cinétique</term><term>Humains</term><term>Inhibiteurs de la cystéine protéinase</term><term>Liaison aux protéines</term><term>Salvia miltiorrhiza</term><term>Ubiquitinylation</term><term>Virus du SRAS</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">In the search for anti-SARS-CoV, tanshinones derived from Salvia miltiorrhiza were found to be specific and selective inhibitors for the SARS-CoV 3CL(pro) and PL(pro), viral cysteine proteases. A literature search for studies involving the seven isolated tanshinone hits showed that at present, none have been identified as coronaviral protease inhibitors. We have identified that all of the isolated tanshinones are good inhibitors of both cysteine proteases. However, their activity was slightly affected by subtle changes in structure and targeting enzymes. All isolated compounds (1-7) act as time dependent inhibitors of PL(pro), but no improved inhibition was observed following preincubation with the 3CL(pro). In a detail kinetic mechanism study, all of the tanshinones except rosmariquinone (7) were identified as noncompetitive enzyme isomerization inhibitors. However, rosmariquinone (7) showed a different kinetic mechanism through mixed-type simple reversible slow-binding inhibition. Furthermore, tanshinone I (5) exhibited the most potent nanomolar level inhibitory activity toward deubiquitinating (IC(50)=0.7 μM). Additionally, the inhibition is selective because these compounds do not exert significant inhibitory effects against other proteases including chymotrysin, papain, and HIV protease. These findings provide potential inhibitors for SARS-CoV viral infection and replication.</div></front></TEI><affiliations><list><country><li>Corée du Sud</li></country></list><tree><noCountry><name sortKey="Jeong, Hyung Jae" sort="Jeong, Hyung Jae" uniqKey="Jeong H" first="Hyung Jae" last="Jeong">Hyung Jae Jeong</name><name sortKey="Kim, Dae Wook" sort="Kim, Dae Wook" uniqKey="Kim D" first="Dae Wook" last="Kim">Dae Wook Kim</name><name sortKey="Kim, Jang Hoon" sort="Kim, Jang Hoon" uniqKey="Kim J" first="Jang Hoon" last="Kim">Jang Hoon Kim</name><name sortKey="Kim, Young Min" sort="Kim, Young Min" uniqKey="Kim Y" first="Young Min" last="Kim">Young Min Kim</name><name sortKey="Kwon, Hyung Jun" sort="Kwon, Hyung Jun" uniqKey="Kwon H" first="Hyung-Jun" last="Kwon">Hyung-Jun Kwon</name><name sortKey="Lee, Woo Song" sort="Lee, Woo Song" uniqKey="Lee W" first="Woo Song" last="Lee">Woo Song Lee</name><name sortKey="Park, Ki Hun" sort="Park, Ki Hun" uniqKey="Park K" first="Ki Hun" last="Park">Ki Hun Park</name><name sortKey="Park, Su Jin" sort="Park, Su Jin" uniqKey="Park S" first="Su-Jin" last="Park">Su-Jin Park</name><name sortKey="Ryu, Young Bae" sort="Ryu, Young Bae" uniqKey="Ryu Y" first="Young Bae" last="Ryu">Young Bae Ryu</name></noCountry><country name="Corée du Sud"><noRegion><name sortKey="Park, Ji Young" sort="Park, Ji Young" uniqKey="Park J" first="Ji-Young" last="Park">Ji-Young Park</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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