2-Sulfonylpyrimidines as Privileged Warheads for the Development of S. aureus Sortase A Inhibitors
- Publikationstyp:
- Zeitschriftenaufsatz
- Metadaten:
-
- Autoren
- Fabian Barthels
- Jessica Meyr
- Stefan J Hammerschmidt
- Tessa Marciniak
- Hans-Joachim Raeder
- Wilma Ziebuhr
- Bernd Engels
- Tanja Schirmeister
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000745148300001&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.3389/fmolb.2021.804970
- eISSN
- 2296-889X
- Externe Identifier
- Clarivate Analytics Document Solution ID: YK3WV
- PubMed Identifier: 35047562
- Zeitschrift
- FRONTIERS IN MOLECULAR BIOSCIENCES
- Schlüsselwörter
- covalent inhibition
- sortase
- quantum mechanics
- anti-virulence
- drug discovery
- Artikelnummer
- ARTN 804970
- Datum der Veröffentlichung
- 2022
- Status
- Published
- Titel
- 2-Sulfonylpyrimidines as Privileged Warheads for the Development of <i>S. aureus</i> Sortase A Inhibitors
- Sub types
- Article
- Ausgabe der Zeitschrift
- 8
Datenquelle: Web of Science (Lite)
- Andere Metadatenquellen:
-
- Abstract
- <jats:p><jats:italic>Staphylococcus aureus</jats:italic> is one of the most frequent causes of nosocomial and community-acquired infections, with emerging multiresistant isolates causing a significant burden to public health systems. We identified 2-sulfonylpyrimidines as a new class of potent inhibitors against <jats:italic>S. aureus</jats:italic> sortase A acting by covalent modification of the active site cysteine 184. Series of derivatives were synthesized to derive structure-activity relationship (SAR) with the most potent compounds displaying low micromolar K<jats:sub>I</jats:sub> values. Studies on the inhibition selectivity of homologous cysteine proteases showed that 2-sulfonylpyrimidines reacted efficiently with protonated cysteine residues as found in sortase A, though surprisingly, no reaction occurred with the more nucleophilic cysteine residue from imidazolinium-thiolate dyads of cathepsin-like proteases. By means of enzymatic and chemical kinetics as well as quantum chemical calculations, it could be rationalized that the <jats:italic>S</jats:italic><jats:sub><jats:italic>N</jats:italic></jats:sub>Ar reaction between protonated cysteine residues and 2-sulfonylpyrimidines proceeds in a concerted fashion, and the mechanism involves a ternary transition state with a conjugated base. Molecular docking and enzyme inhibition at variable pH values allowed us to hypothesize that in sortase A this base is represented by the catalytic histidine 120, which could be substantiated by QM model calculation with 4-methylimidazole as histidine analog.</jats:p>
- Autoren
- Fabian Barthels
- Jessica Meyr
- Stefan J Hammerschmidt
- Tessa Marciniak
- Hans-Joachim Räder
- Wilma Ziebuhr
- Bernd Engels
- Tanja Schirmeister
- DOI
- 10.3389/fmolb.2021.804970
- eISSN
- 2296-889X
- Zeitschrift
- Frontiers in Molecular Biosciences
- Online publication date
- 2022
- Status
- Published online
- Herausgeber
- Frontiers Media SA
- Herausgeber URL
- http://dx.doi.org/10.3389/fmolb.2021.804970
- Datum der Datenerfassung
- 2022
- Titel
- 2-Sulfonylpyrimidines as Privileged Warheads for the Development of S. aureus Sortase A Inhibitors
- Ausgabe der Zeitschrift
- 8
Datenquelle: Crossref
- Abstract
- <i>Staphylococcus aureus</i> is one of the most frequent causes of nosocomial and community-acquired infections, with emerging multiresistant isolates causing a significant burden to public health systems. We identified 2-sulfonylpyrimidines as a new class of potent inhibitors against <i>S. aureus</i> sortase A acting by covalent modification of the active site cysteine 184. Series of derivatives were synthesized to derive structure-activity relationship (SAR) with the most potent compounds displaying low micromolar K<sub>I</sub> values. Studies on the inhibition selectivity of homologous cysteine proteases showed that 2-sulfonylpyrimidines reacted efficiently with protonated cysteine residues as found in sortase A, though surprisingly, no reaction occurred with the more nucleophilic cysteine residue from imidazolinium-thiolate dyads of cathepsin-like proteases. By means of enzymatic and chemical kinetics as well as quantum chemical calculations, it could be rationalized that the <i>S</i> <sub><i>N</i></sub> Ar reaction between protonated cysteine residues and 2-sulfonylpyrimidines proceeds in a concerted fashion, and the mechanism involves a ternary transition state with a conjugated base. Molecular docking and enzyme inhibition at variable pH values allowed us to hypothesize that in sortase A this base is represented by the catalytic histidine 120, which could be substantiated by QM model calculation with 4-methylimidazole as histidine analog.
- Addresses
- Institute for Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-University, Mainz, Germany.
- Autoren
- Fabian Barthels
- Jessica Meyr
- Stefan J Hammerschmidt
- Tessa Marciniak
- Hans-Joachim Räder
- Wilma Ziebuhr
- Bernd Engels
- Tanja Schirmeister
- DOI
- 10.3389/fmolb.2021.804970
- eISSN
- 2296-889X
- Externe Identifier
- PubMed Identifier: 35047562
- PubMed Central ID: PMC8763382
- Funding acknowledgements
- Bundesministerium für Bildung und Forschung:
- Deutsche Forschungsgemeinschaft:
- Open access
- true
- ISSN
- 2296-889X
- Zeitschrift
- Frontiers in molecular biosciences
- Sprache
- eng
- Medium
- Electronic-eCollection
- Online publication date
- 2022
- Open access status
- Open Access
- Paginierung
- 804970
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2022
- Titel
- 2-Sulfonylpyrimidines as Privileged Warheads for the Development of <i>S. aureus</i> Sortase A Inhibitors.
- Sub types
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 8
Files
https://www.frontiersin.org/articles/10.3389/fmolb.2021.804970/pdf https://europepmc.org/articles/PMC8763382?pdf=render
Datenquelle: Europe PubMed Central
- Abstract
- Staphylococcus aureus is one of the most frequent causes of nosocomial and community-acquired infections, with emerging multiresistant isolates causing a significant burden to public health systems. We identified 2-sulfonylpyrimidines as a new class of potent inhibitors against S. aureus sortase A acting by covalent modification of the active site cysteine 184. Series of derivatives were synthesized to derive structure-activity relationship (SAR) with the most potent compounds displaying low micromolar KI values. Studies on the inhibition selectivity of homologous cysteine proteases showed that 2-sulfonylpyrimidines reacted efficiently with protonated cysteine residues as found in sortase A, though surprisingly, no reaction occurred with the more nucleophilic cysteine residue from imidazolinium-thiolate dyads of cathepsin-like proteases. By means of enzymatic and chemical kinetics as well as quantum chemical calculations, it could be rationalized that the S N Ar reaction between protonated cysteine residues and 2-sulfonylpyrimidines proceeds in a concerted fashion, and the mechanism involves a ternary transition state with a conjugated base. Molecular docking and enzyme inhibition at variable pH values allowed us to hypothesize that in sortase A this base is represented by the catalytic histidine 120, which could be substantiated by QM model calculation with 4-methylimidazole as histidine analog.
- Date of acceptance
- 2021
- Autoren
- Fabian Barthels
- Jessica Meyr
- Stefan J Hammerschmidt
- Tessa Marciniak
- Hans-Joachim Räder
- Wilma Ziebuhr
- Bernd Engels
- Tanja Schirmeister
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/35047562
- DOI
- 10.3389/fmolb.2021.804970
- Externe Identifier
- PubMed Central ID: PMC8763382
- ISSN
- 2296-889X
- Zeitschrift
- Front Mol Biosci
- Schlüsselwörter
- anti-virulence
- covalent inhibition
- drug discovery
- quantum mechanics
- sortase
- Sprache
- eng
- Country
- Switzerland
- Paginierung
- 804970
- PII
- 804970
- Datum der Veröffentlichung
- 2021
- Status
- Published online
- Titel
- 2-Sulfonylpyrimidines as Privileged Warheads for the Development of S. aureus Sortase A Inhibitors.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 8
Datenquelle: PubMed
- Author's licence
- CC-BY
- Autoren
- Fabian Barthels
- Jessica Meyr
- Stefan J Hammerschmidt
- Tessa Marciniak
- Hans-Joachim Räder
- Wilma Ziebuhr
- Bernd Engels
- Tanja Schirmeister
- Hosting institution
- Universitätsbibliothek Mainz
- Sammlungen
- JGU-Publikationen
- Resource version
- Published version
- DOI
- 10.3389/fmolb.2021.804970
- File(s) embargoed
- false
- Open access
- true
- ISSN
- 2296-889X
- Zeitschrift
- Frontiers in molecular biosciences
- Schlüsselwörter
- 570 Biowissenschaften
- 570 Life sciences
- 610 Medizin
- 610 Medical sciences
- Sprache
- eng
- Open access status
- Open Access
- Paginierung
- 804970
- Datum der Veröffentlichung
- 2021
- Public URL
- https://openscience.ub.uni-mainz.de/handle/20.500.12030/8889
- Herausgeber
- Frontiers
- Datum der Datenerfassung
- 2023
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2023
- Zugang
- Public
- Titel
- 2-sulfonylpyrimidines as privileged warheads for the development of S. aureus sortase A inhibitors
- Ausgabe der Zeitschrift
- 8
Files
2sulfonylpyrimidines_as_privi-20230302115838017.pdf
Datenquelle: OPENSCIENCE.UB
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