Proline-Based Allosteric Inhibitors of Zika and Dengue Virus NS2B/NS3 Proteases
- Publikationstyp:
- Zeitschriftenaufsatz
- Metadaten:
-
- Autoren
- Benedikt Millies
- Franziska von Hammerstein
- Andrea Gellert
- Stefan Hammerschmidt
- Fabian Barthels
- Ulrike Goeppel
- Melissa Immerheiser
- Fabian Elgner
- Nathalie Jung
- Michael Basic
- Christian Kersten
- Werner Kiefer
- Jochen Bodem
- Eberhard Hildt
- Maike Windbergs
- Ute A Hellmich
- Tanja Schirmeister
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000505633400026&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1021/acs.jmedchem.9b01697
- eISSN
- 1520-4804
- Externe Identifier
- Clarivate Analytics Document Solution ID: KA2NE
- PubMed Identifier: 31769670
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 24
- Zeitschrift
- JOURNAL OF MEDICINAL CHEMISTRY
- Paginierung
- 11359 - 11382
- Datum der Veröffentlichung
- 2019
- Status
- Published
- Titel
- Proline-Based Allosteric Inhibitors of Zika and Dengue Virus NS2B/NS3 Proteases
- Sub types
- Article
- Ausgabe der Zeitschrift
- 62
Datenquelle: Web of Science (Lite)
- Andere Metadatenquellen:
-
- Autoren
- Benedikt Millies
- Franziska von Hammerstein
- Andrea Gellert
- Stefan Hammerschmidt
- Fabian Barthels
- Ulrike Göppel
- Melissa Immerheiser
- Fabian Elgner
- Nathalie Jung
- Michael Basic
- Christian Kersten
- Werner Kiefer
- Jochen Bodem
- Eberhard Hildt
- Maike Windbergs
- Ute A Hellmich
- Tanja Schirmeister
- DOI
- 10.1021/acs.jmedchem.9b01697
- eISSN
- 1520-4804
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 24
- Zeitschrift
- Journal of Medicinal Chemistry
- Sprache
- en
- Online publication date
- 2019
- Paginierung
- 11359 - 11382
- Datum der Veröffentlichung
- 2019
- Status
- Published
- Herausgeber
- American Chemical Society (ACS)
- Herausgeber URL
- http://dx.doi.org/10.1021/acs.jmedchem.9b01697
- Datum der Datenerfassung
- 2023
- Titel
- Proline-Based Allosteric Inhibitors of Zika and Dengue Virus NS2B/NS3 Proteases
- Ausgabe der Zeitschrift
- 62
Datenquelle: Crossref
- Abstract
- The NS2B/NS3 serine proteases of the Zika and Dengue flaviviruses are attractive targets for the development of antiviral drugs. We report the synthesis and evaluation of a new, proline-based compound class that displays allosteric inhibition of both proteases. The structural features relevant for protease binding and inhibition were determined to establish them as new lead compounds for flaviviral inhibitors. Based on our structure-activity relationship studies, the molecules were further optimized, leading to inhibitors with submicromolar IC<sub>50</sub> values and improved lipophilic ligand efficiency. The allosteric binding site in the proteases was probed using mutagenesis and covalent modification of the obtained cysteine mutants with maleimides, followed by computational elucidation of the possible binding modes. In infected cells, antiviral activity against Dengue virus serotype 2 using prodrugs of the inhibitors was observed. In summary, a novel inhibitor scaffold targeting an allosteric site shared between flaviviral NS2B/NS3 proteases is presented whose efficacy is demonstrated in vitro and in cellulo.
- Addresses
- Institute of Pharmacy and Biochemistry , Johannes Gutenberg University Mainz , Staudinger Weg 5 , 55128 Mainz , Germany.
- Autoren
- Benedikt Millies
- Franziska von Hammerstein
- Andrea Gellert
- Stefan Hammerschmidt
- Fabian Barthels
- Ulrike Göppel
- Melissa Immerheiser
- Fabian Elgner
- Nathalie Jung
- Michael Basic
- Christian Kersten
- Werner Kiefer
- Jochen Bodem
- Eberhard Hildt
- Maike Windbergs
- Ute A Hellmich
- Tanja Schirmeister
- DOI
- 10.1021/acs.jmedchem.9b01697
- eISSN
- 1520-4804
- Externe Identifier
- PubMed Identifier: 31769670
- Funding acknowledgements
- LOEWE Center DRUID:
- State of Hessen:
- Carl-Zeiss-Stiftung:
- Open access
- false
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 24
- Zeitschrift
- Journal of medicinal chemistry
- Schlüsselwörter
- Humans
- Dengue Virus
- Dengue
- Peptide Hydrolases
- Serine Endopeptidases
- Proline
- Viral Proteins
- Viral Nonstructural Proteins
- Protease Inhibitors
- Antiviral Agents
- Allosteric Regulation
- Allosteric Site
- Catalytic Domain
- Protein Conformation
- Protein Binding
- Structure-Activity Relationship
- Molecular Docking Simulation
- Zika Virus
- Zika Virus Infection
- A549 Cells
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2019
- Paginierung
- 11359 - 11382
- Datum der Veröffentlichung
- 2019
- Status
- Published
- Datum der Datenerfassung
- 2019
- Titel
- Proline-Based Allosteric Inhibitors of Zika and Dengue Virus NS2B/NS3 Proteases.
- Sub types
- Research Support, Non-U.S. Gov't
- Journal Article
- Ausgabe der Zeitschrift
- 62
Datenquelle: Europe PubMed Central
- Abstract
- The NS2B/NS3 serine proteases of the Zika and Dengue flaviviruses are attractive targets for the development of antiviral drugs. We report the synthesis and evaluation of a new, proline-based compound class that displays allosteric inhibition of both proteases. The structural features relevant for protease binding and inhibition were determined to establish them as new lead compounds for flaviviral inhibitors. Based on our structure-activity relationship studies, the molecules were further optimized, leading to inhibitors with submicromolar IC50 values and improved lipophilic ligand efficiency. The allosteric binding site in the proteases was probed using mutagenesis and covalent modification of the obtained cysteine mutants with maleimides, followed by computational elucidation of the possible binding modes. In infected cells, antiviral activity against Dengue virus serotype 2 using prodrugs of the inhibitors was observed. In summary, a novel inhibitor scaffold targeting an allosteric site shared between flaviviral NS2B/NS3 proteases is presented whose efficacy is demonstrated in vitro and in cellulo.
- Autoren
- Benedikt Millies
- Franziska von Hammerstein
- Andrea Gellert
- Stefan Hammerschmidt
- Fabian Barthels
- Ulrike Göppel
- Melissa Immerheiser
- Fabian Elgner
- Nathalie Jung
- Michael Basic
- Christian Kersten
- Werner Kiefer
- Jochen Bodem
- Eberhard Hildt
- Maike Windbergs
- Ute A Hellmich
- Tanja Schirmeister
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/31769670
- DOI
- 10.1021/acs.jmedchem.9b01697
- eISSN
- 1520-4804
- Ausgabe der Veröffentlichung
- 24
- Zeitschrift
- J Med Chem
- Schlüsselwörter
- A549 Cells
- Allosteric Regulation
- Allosteric Site
- Antiviral Agents
- Catalytic Domain
- Dengue
- Dengue Virus
- Humans
- Molecular Docking Simulation
- Peptide Hydrolases
- Proline
- Protease Inhibitors
- Protein Binding
- Protein Conformation
- Serine Endopeptidases
- Structure-Activity Relationship
- Viral Nonstructural Proteins
- Viral Proteins
- Zika Virus
- Zika Virus Infection
- Sprache
- eng
- Country
- United States
- Paginierung
- 11359 - 11382
- Datum der Veröffentlichung
- 2019
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2020
- Titel
- Proline-Based Allosteric Inhibitors of Zika and Dengue Virus NS2B/NS3 Proteases.
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 62
Datenquelle: PubMed
- Beziehungen:
- Eigentum von