Identification of a Novel Inhibitor against Middle East Respiratory Syndrome Coronavirus
Identifieur interne : 000D50 ( Main/Exploration ); précédent : 000D49; suivant : 000D51Identification of a Novel Inhibitor against Middle East Respiratory Syndrome Coronavirus
Auteurs : Yaping Sun [République populaire de Chine] ; Huaidong Zhang ; Jian Shi ; Zhe Zhang ; Rui GongSource :
- Viruses [ 1999-4915 ] ; 2017.
Descripteurs français
- KwdFr :
- Antiviraux (), Antiviraux (pharmacologie), Antiviraux (synthèse chimique), Coronavirus du syndrome respiratoire du Moyen-Orient (), Coronavirus du syndrome respiratoire du Moyen-Orient (physiologie), Cristallisation, Découverte de médicament, Fusion membranaire (), Glycoprotéine de spicule des coronavirus (), Glycoprotéine de spicule des coronavirus (métabolisme), Humains, Infections à coronavirus (traitement médicamenteux), Infections à coronavirus (virologie), Liaison aux protéines, Peptides (), Peptides (métabolisme), Peptides (pharmacologie), Protéines de fusion virale (), Protéines de fusion virale (antagonistes et inhibiteurs), Pénétration virale (), Récepteurs viraux (métabolisme), Structure secondaire des protéines.
- MESH :
- antagonistes et inhibiteurs : Protéines de fusion virale.
- métabolisme : Glycoprotéine de spicule des coronavirus, Peptides, Récepteurs viraux.
- pharmacologie : Antiviraux, Peptides.
- physiologie : Coronavirus du syndrome respiratoire du Moyen-Orient.
- synthèse chimique : Antiviraux.
- traitement médicamenteux : Infections à coronavirus.
- virologie : Infections à coronavirus.
- Antiviraux, Coronavirus du syndrome respiratoire du Moyen-Orient, Cristallisation, Découverte de médicament, Fusion membranaire, Glycoprotéine de spicule des coronavirus, Humains, Liaison aux protéines, Peptides, Protéines de fusion virale, Pénétration virale, Structure secondaire des protéines.
English descriptors
- KwdEn :
- Antiviral Agents (chemical synthesis), Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Coronavirus Infections (drug therapy), Coronavirus Infections (virology), Crystallization, Drug Discovery, Humans, Membrane Fusion (drug effects), Middle East Respiratory Syndrome Coronavirus (chemistry), Middle East Respiratory Syndrome Coronavirus (drug effects), Middle East Respiratory Syndrome Coronavirus (physiology), Peptides (chemistry), Peptides (metabolism), Peptides (pharmacology), Protein Binding, Protein Structure, Secondary, Receptors, Virus (metabolism), Spike Glycoprotein, Coronavirus (chemistry), Spike Glycoprotein, Coronavirus (metabolism), Viral Fusion Proteins (antagonists & inhibitors), Viral Fusion Proteins (chemistry), Virus Internalization (drug effects).
- MESH :
- chemical , antagonists & inhibitors : Viral Fusion Proteins.
- chemical , chemical synthesis : Antiviral Agents.
- chemical , chemistry : Antiviral Agents, Peptides, Spike Glycoprotein, Coronavirus, Viral Fusion Proteins.
- chemical , metabolism : Peptides, Receptors, Virus, Spike Glycoprotein, Coronavirus.
- chemical , pharmacology : Antiviral Agents, Peptides.
- chemistry : Middle East Respiratory Syndrome Coronavirus.
- drug effects : Membrane Fusion, Middle East Respiratory Syndrome Coronavirus, Virus Internalization.
- drug therapy : Coronavirus Infections.
- physiology : Middle East Respiratory Syndrome Coronavirus.
- virology : Coronavirus Infections.
- Crystallization, Drug Discovery, Humans, Protein Binding, Protein Structure, Secondary.
Abstract
The Middle East respiratory syndrome coronavirus (MERS-CoV) was first isolated in 2012, and circulated worldwide with high mortality. The continual outbreaks of MERS-CoV highlight the importance of developing antiviral therapeutics. Here, we rationally designed a novel fusion inhibitor named MERS-five-helix bundle (MERS-5HB) derived from the six-helix bundle (MERS-6HB) which was formed by the process of membrane fusion. MERS-5HB consists of three copies of heptad repeat 1 (HR1) and two copies of heptad repeat 2 (HR2) while MERS-6HB includes three copies each of HR1 and HR2. As it lacks one HR2, MERS-5HB was expected to interact with viral HR2 to interrupt the fusion step. What we found was that MERS-5HB could bind to HR2P, a peptide derived from HR2, with a strong affinity value (
Url:
DOI: 10.3390/v9090255
PubMed: 28906430
PubMed Central: 5618021
Affiliations:
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Le document en format XML
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Hong Shan, Wuhan 430071, China;<email>sunypxw@163.com</email> (Y.S.);<email>hdzhang@wh.iov.cn</email> (H.Z.);<email>shijian@wh.iov.cn</email> (J.S.);<email>zhangzhe@wh.iov.cn</email> (Z.Z.)</nlm:aff></affiliation></author><author><name sortKey="Zhang, Zhe" sort="Zhang, Zhe" uniqKey="Zhang Z" first="Zhe" last="Zhang">Zhe Zhang</name><affiliation><nlm:aff id="af1-viruses-09-00255">Center for Emerging Infectious Diseases, CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan 430071, China;<email>sunypxw@163.com</email> (Y.S.);<email>hdzhang@wh.iov.cn</email> (H.Z.);<email>shijian@wh.iov.cn</email> (J.S.);<email>zhangzhe@wh.iov.cn</email> (Z.Z.)</nlm:aff></affiliation></author><author><name sortKey="Gong, Rui" sort="Gong, Rui" uniqKey="Gong R" first="Rui" last="Gong">Rui Gong</name><affiliation><nlm:aff id="af1-viruses-09-00255">Center for Emerging Infectious Diseases, CAS Key Laboratory of Special 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Inhibitor against Middle East Respiratory Syndrome Coronavirus</title><author><name sortKey="Sun, Yaping" sort="Sun, Yaping" uniqKey="Sun Y" first="Yaping" last="Sun">Yaping Sun</name><affiliation><nlm:aff id="af1-viruses-09-00255">Center for Emerging Infectious Diseases, CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan 430071, China;<email>sunypxw@163.com</email> (Y.S.);<email>hdzhang@wh.iov.cn</email> (H.Z.);<email>shijian@wh.iov.cn</email> (J.S.);<email>zhangzhe@wh.iov.cn</email> (Z.Z.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-viruses-09-00255">University of Chinese Academy of Sciences, Beijing 100049, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>University of Chinese Academy of Sciences, Beijing 100049</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Zhang, Huaidong" sort="Zhang, Huaidong" uniqKey="Zhang H" first="Huaidong" last="Zhang">Huaidong Zhang</name><affiliation><nlm:aff id="af1-viruses-09-00255">Center for Emerging Infectious Diseases, CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan 430071, China;<email>sunypxw@163.com</email> (Y.S.);<email>hdzhang@wh.iov.cn</email> (H.Z.);<email>shijian@wh.iov.cn</email> (J.S.);<email>zhangzhe@wh.iov.cn</email> (Z.Z.)</nlm:aff></affiliation></author><author><name sortKey="Shi, Jian" sort="Shi, Jian" uniqKey="Shi J" first="Jian" last="Shi">Jian Shi</name><affiliation><nlm:aff id="af1-viruses-09-00255">Center for Emerging Infectious Diseases, CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan 430071, China;<email>sunypxw@163.com</email> (Y.S.);<email>hdzhang@wh.iov.cn</email> (H.Z.);<email>shijian@wh.iov.cn</email> (J.S.);<email>zhangzhe@wh.iov.cn</email> (Z.Z.)</nlm:aff></affiliation></author><author><name sortKey="Zhang, Zhe" sort="Zhang, Zhe" uniqKey="Zhang Z" first="Zhe" last="Zhang">Zhe Zhang</name><affiliation><nlm:aff id="af1-viruses-09-00255">Center for Emerging Infectious Diseases, CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan 430071, China;<email>sunypxw@163.com</email> (Y.S.);<email>hdzhang@wh.iov.cn</email> (H.Z.);<email>shijian@wh.iov.cn</email> (J.S.);<email>zhangzhe@wh.iov.cn</email> (Z.Z.)</nlm:aff></affiliation></author><author><name sortKey="Gong, Rui" sort="Gong, Rui" uniqKey="Gong R" first="Rui" last="Gong">Rui Gong</name><affiliation><nlm:aff id="af1-viruses-09-00255">Center for Emerging Infectious Diseases, CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan 430071, China;<email>sunypxw@163.com</email> (Y.S.);<email>hdzhang@wh.iov.cn</email> (H.Z.);<email>shijian@wh.iov.cn</email> (J.S.);<email>zhangzhe@wh.iov.cn</email> (Z.Z.)</nlm:aff></affiliation></author></analytic><series><title level="j">Viruses</title><idno type="eISSN">1999-4915</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral Agents (chemical synthesis)</term><term>Antiviral Agents (chemistry)</term><term>Antiviral Agents (pharmacology)</term><term>Coronavirus Infections (drug therapy)</term><term>Coronavirus Infections (virology)</term><term>Crystallization</term><term>Drug Discovery</term><term>Humans</term><term>Membrane Fusion (drug effects)</term><term>Middle East Respiratory Syndrome Coronavirus (chemistry)</term><term>Middle East Respiratory Syndrome Coronavirus (drug effects)</term><term>Middle East Respiratory Syndrome Coronavirus (physiology)</term><term>Peptides (chemistry)</term><term>Peptides (metabolism)</term><term>Peptides (pharmacology)</term><term>Protein Binding</term><term>Protein Structure, Secondary</term><term>Receptors, Virus (metabolism)</term><term>Spike Glycoprotein, Coronavirus (chemistry)</term><term>Spike Glycoprotein, Coronavirus (metabolism)</term><term>Viral Fusion Proteins (antagonists & inhibitors)</term><term>Viral Fusion Proteins (chemistry)</term><term>Virus Internalization (drug effects)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Antiviraux ()</term><term>Antiviraux (pharmacologie)</term><term>Antiviraux (synthèse chimique)</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient ()</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient (physiologie)</term><term>Cristallisation</term><term>Découverte de médicament</term><term>Fusion membranaire ()</term><term>Glycoprotéine de spicule des coronavirus ()</term><term>Glycoprotéine de spicule des coronavirus (métabolisme)</term><term>Humains</term><term>Infections à coronavirus (traitement médicamenteux)</term><term>Infections à coronavirus (virologie)</term><term>Liaison aux protéines</term><term>Peptides ()</term><term>Peptides (métabolisme)</term><term>Peptides (pharmacologie)</term><term>Protéines de fusion virale ()</term><term>Protéines de fusion virale (antagonistes et inhibiteurs)</term><term>Pénétration virale ()</term><term>Récepteurs viraux (métabolisme)</term><term>Structure secondaire des protéines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Viral Fusion Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Antiviral Agents</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term><term>Peptides</term><term>Spike Glycoprotein, Coronavirus</term><term>Viral Fusion Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Peptides</term><term>Receptors, Virus</term><term>Spike Glycoprotein, Coronavirus</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term><term>Peptides</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines de fusion virale</term></keywords><keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>Middle East Respiratory Syndrome Coronavirus</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Membrane Fusion</term><term>Middle East Respiratory Syndrome Coronavirus</term><term>Virus Internalization</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Coronavirus Infections</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Glycoprotéine de spicule des coronavirus</term><term>Peptides</term><term>Récepteurs viraux</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term><term>Peptides</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Middle East Respiratory Syndrome Coronavirus</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Antiviraux</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Infections à coronavirus</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Infections à coronavirus</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Coronavirus Infections</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Crystallization</term><term>Drug Discovery</term><term>Humans</term><term>Protein Binding</term><term>Protein Structure, Secondary</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Antiviraux</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term><term>Cristallisation</term><term>Découverte de médicament</term><term>Fusion membranaire</term><term>Glycoprotéine de spicule des coronavirus</term><term>Humains</term><term>Liaison aux protéines</term><term>Peptides</term><term>Protéines de fusion virale</term><term>Pénétration virale</term><term>Structure secondaire des protéines</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The Middle East respiratory syndrome coronavirus (MERS-CoV) was first isolated in 2012, and circulated worldwide with high mortality. The continual outbreaks of MERS-CoV highlight the importance of developing antiviral therapeutics. Here, we rationally designed a novel fusion inhibitor named MERS-five-helix bundle (MERS-5HB) derived from the six-helix bundle (MERS-6HB) which was formed by the process of membrane fusion. MERS-5HB consists of three copies of heptad repeat 1 (HR1) and two copies of heptad repeat 2 (HR2) while MERS-6HB includes three copies each of HR1 and HR2. As it lacks one HR2, MERS-5HB was expected to interact with viral HR2 to interrupt the fusion step. What we found was that MERS-5HB could bind to HR2P, a peptide derived from HR2, with a strong affinity value (<italic>K</italic><sub>D</sub>) of up to 0.24 nM. Subsequent assays indicated that MERS-5HB could inhibit pseudotyped MERS-CoV entry effectively with 50% inhibitory concentration (IC<sub>50</sub>) of about 1 μM. In addition, MERS-5HB significantly inhibited spike (S) glycoprotein-mediated syncytial formation in a dose-dependent manner. Further biophysical characterization showed that MERS-5HB was a thermo-stable α-helical secondary structure. The inhibitory potency of MERS-5HB may provide an attractive basis for identification of a novel inhibitor against MERS-CoV, as a potential antiviral agent.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Zaki, A M" uniqKey="Zaki A">A.M. Zaki</name></author><author><name sortKey="Van Boheemen, S" uniqKey="Van Boheemen S">S. van Boheemen</name></author><author><name sortKey="Bestebroer, T M" uniqKey="Bestebroer T">T.M. Bestebroer</name></author><author><name sortKey="Osterhaus, A D" uniqKey="Osterhaus A">A.D. Osterhaus</name></author><author><name sortKey="Fouchier, R A" uniqKey="Fouchier R">R.A. Fouchier</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Drosten, C" uniqKey="Drosten C">C. Drosten</name></author><author><name sortKey="Gunther, S" uniqKey="Gunther S">S. 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Hamer</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>République populaire de Chine</li></country><settlement><li>Pékin</li></settlement></list><tree><noCountry><name sortKey="Gong, Rui" sort="Gong, Rui" uniqKey="Gong R" first="Rui" last="Gong">Rui Gong</name><name sortKey="Shi, Jian" sort="Shi, Jian" uniqKey="Shi J" first="Jian" last="Shi">Jian Shi</name><name sortKey="Zhang, Huaidong" sort="Zhang, Huaidong" uniqKey="Zhang H" first="Huaidong" last="Zhang">Huaidong Zhang</name><name sortKey="Zhang, Zhe" sort="Zhang, Zhe" uniqKey="Zhang Z" first="Zhe" last="Zhang">Zhe Zhang</name></noCountry><country name="République populaire de Chine"><noRegion><name sortKey="Sun, Yaping" sort="Sun, Yaping" uniqKey="Sun Y" first="Yaping" last="Sun">Yaping Sun</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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