Allosteric Inhibitors of Zika Virus NS2B-NS3 Protease Targeting Protease in “Super-Open” Conformation
The Zika virus (ZIKV), a member of the Flaviviridae family, is considered a major health threat causing multiple cases of microcephaly in newborns and Guillain-Barré syndrome in adults. In this study, we targeted a transient, deep, and hydrophobic pocket of the “super-open” conformation of ZIKV NS2B...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-04-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/15/5/1106 |
| _version_ | 1797598119000539136 |
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| author | Ittipat Meewan Sergey A. Shiryaev Julius Kattoula Chun-Teng Huang Vivian Lin Chiao-Han Chuang Alexey V. Terskikh Ruben Abagyan |
| author_facet | Ittipat Meewan Sergey A. Shiryaev Julius Kattoula Chun-Teng Huang Vivian Lin Chiao-Han Chuang Alexey V. Terskikh Ruben Abagyan |
| author_sort | Ittipat Meewan |
| collection | DOAJ |
| description | The Zika virus (ZIKV), a member of the Flaviviridae family, is considered a major health threat causing multiple cases of microcephaly in newborns and Guillain-Barré syndrome in adults. In this study, we targeted a transient, deep, and hydrophobic pocket of the “super-open” conformation of ZIKV NS2B-NS3 protease to overcome the limitations of the active site pocket. After virtual docking screening of approximately seven million compounds against the novel allosteric site, we selected the top six candidates and assessed them in enzymatic assays. Six candidates inhibited ZIKV NS2B-NS3 protease proteolytic activity at low micromolar concentrations. These six compounds, targeting the selected protease pocket conserved in ZIKV, serve as unique drug candidates and open new opportunities for possible treatment against several flavivirus infections. |
| first_indexed | 2024-03-11T03:14:49Z |
| format | Article |
| id | doaj.art-d82dfc16c47e4ce8a8d1bcd1aada43df |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-11T03:14:49Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-d82dfc16c47e4ce8a8d1bcd1aada43df2023-11-18T03:39:05ZengMDPI AGViruses1999-49152023-04-01155110610.3390/v15051106Allosteric Inhibitors of Zika Virus NS2B-NS3 Protease Targeting Protease in “Super-Open” ConformationIttipat Meewan0Sergey A. Shiryaev1Julius Kattoula2Chun-Teng Huang3Vivian Lin4Chiao-Han Chuang5Alexey V. Terskikh6Ruben Abagyan7Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, ThailandSanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USASkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USASanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USASanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USASanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USASanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USASkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USAThe Zika virus (ZIKV), a member of the Flaviviridae family, is considered a major health threat causing multiple cases of microcephaly in newborns and Guillain-Barré syndrome in adults. In this study, we targeted a transient, deep, and hydrophobic pocket of the “super-open” conformation of ZIKV NS2B-NS3 protease to overcome the limitations of the active site pocket. After virtual docking screening of approximately seven million compounds against the novel allosteric site, we selected the top six candidates and assessed them in enzymatic assays. Six candidates inhibited ZIKV NS2B-NS3 protease proteolytic activity at low micromolar concentrations. These six compounds, targeting the selected protease pocket conserved in ZIKV, serve as unique drug candidates and open new opportunities for possible treatment against several flavivirus infections.https://www.mdpi.com/1999-4915/15/5/1106Zika virus protease inhibitorsallosteric inhibitorsZika virus NS2B-NS3 proteasesuper-open conformation |
| spellingShingle | Ittipat Meewan Sergey A. Shiryaev Julius Kattoula Chun-Teng Huang Vivian Lin Chiao-Han Chuang Alexey V. Terskikh Ruben Abagyan Allosteric Inhibitors of Zika Virus NS2B-NS3 Protease Targeting Protease in “Super-Open” Conformation Viruses Zika virus protease inhibitors allosteric inhibitors Zika virus NS2B-NS3 protease super-open conformation |
| title | Allosteric Inhibitors of Zika Virus NS2B-NS3 Protease Targeting Protease in “Super-Open” Conformation |
| title_full | Allosteric Inhibitors of Zika Virus NS2B-NS3 Protease Targeting Protease in “Super-Open” Conformation |
| title_fullStr | Allosteric Inhibitors of Zika Virus NS2B-NS3 Protease Targeting Protease in “Super-Open” Conformation |
| title_full_unstemmed | Allosteric Inhibitors of Zika Virus NS2B-NS3 Protease Targeting Protease in “Super-Open” Conformation |
| title_short | Allosteric Inhibitors of Zika Virus NS2B-NS3 Protease Targeting Protease in “Super-Open” Conformation |
| title_sort | allosteric inhibitors of zika virus ns2b ns3 protease targeting protease in super open conformation |
| topic | Zika virus protease inhibitors allosteric inhibitors Zika virus NS2B-NS3 protease super-open conformation |
| url | https://www.mdpi.com/1999-4915/15/5/1106 |
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