Structure-Based Design of High-Affinity and Selective Peptidomimetic Hepsin Inhibitors

Publikationstyp:
Zeitschriftenaufsatz
Metadaten:
Autoren
  • Philip Maximilian Knaff
  • Patrick Mueller
  • Christian Kersten
  • Lukas Wettstein
  • Jan Muench
  • Katharina Landfester
  • Volker Mailaender
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000813687600001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1021/acs.biomac.1c01011
eISSN
1526-4602
Externe Identifier
  • Clarivate Analytics Document Solution ID: 2G6FF
  • PubMed Identifier: 35593713
ISSN
1525-7797
Ausgabe der Veröffentlichung
6
Zeitschrift
BIOMACROMOLECULES
Paginierung
2236 - 2242
Datum der Veröffentlichung
2022
Status
Published
Titel
Structure-Based Design of High-Affinity and Selective Peptidomimetic Hepsin Inhibitors
Sub types
  • Article
Ausgabe der Zeitschrift
23

Datenquelle: Web of Science (Lite)

Andere Metadatenquellen:
Autoren
  • Philip Maximilian Knaff
  • Patrick Müller
  • Christian Kersten
  • Lukas Wettstein
  • Jan Münch
  • Katharina Landfester
  • Volker Mailänder
DOI
10.1021/acs.biomac.1c01011
eISSN
1526-4602
ISSN
1525-7797
Ausgabe der Veröffentlichung
6
Zeitschrift
Biomacromolecules
Sprache
en
Online publication date
2022
Paginierung
2236 - 2242
Datum der Veröffentlichung
2022
Status
Published
Herausgeber
American Chemical Society (ACS)
Herausgeber URL
http://dx.doi.org/10.1021/acs.biomac.1c01011
Datum der Datenerfassung
2023
Titel
Structure-Based Design of High-Affinity and Selective Peptidomimetic Hepsin Inhibitors
Ausgabe der Zeitschrift
23

Datenquelle: Crossref

Abstract
In many solid tumors, increased upregulation of transmembrane serine proteases (TTSPs) leads to an overactivation of growth factors, which promotes tumor progression. Here, we have used a combinatorial methodology to develop high-affinity tetrapeptidic inhibitors. A previous virtual screening of 8000 peptide combinations against the crystal structure of the TTSP hepsin identified a series of recognition sequences, customized for the non-prime substrate binding (P) sites of this serine protease. A combination of the top recognition sequences with an electrophilic warhead resulted in highly potent inhibitors with good selectivity against coagulation proteases factor Xa and thrombin. Structure-activity relationships of two selected compounds were further elucidated by investigation of their stability in biological fluids as well as the influence of the warhead and truncated inhibitors on the inhibitory potency. Overall, this methodology yielded compounds as selective inhibitors for potential cancer drug development, where hepsin is overexpressed.
Addresses
  • Max Planck Institute for Polymer Research, Ackermannweg 10, Mainz 55128, Germany.
Autoren
  • Philip Maximilian Knaff
  • Patrick Müller
  • Christian Kersten
  • Lukas Wettstein
  • Jan Münch
  • Katharina Landfester
  • Volker Mailänder
DOI
10.1021/acs.biomac.1c01011
eISSN
1526-4602
Externe Identifier
  • PubMed Identifier: 35593713
Funding acknowledgements
  • Deutsche Forschungsgemeinschaft: MA3271/10-1
  • Deutsche Forschungsgemeinschaft: CRC1066
Open access
false
ISSN
1525-7797
Ausgabe der Veröffentlichung
6
Zeitschrift
Biomacromolecules
Schlüsselwörter
  • Serine Endopeptidases
  • Serine Proteinase Inhibitors
  • Structure-Activity Relationship
  • Drug Design
  • Serine Proteases
  • Peptidomimetics
Sprache
eng
Medium
Print-Electronic
Online publication date
2022
Paginierung
2236 - 2242
Datum der Veröffentlichung
2022
Status
Published
Datum der Datenerfassung
2022
Titel
Structure-Based Design of High-Affinity and Selective Peptidomimetic Hepsin Inhibitors.
Sub types
  • Research Support, Non-U.S. Gov't
  • Journal Article
Ausgabe der Zeitschrift
23

Datenquelle: Europe PubMed Central

Abstract
In many solid tumors, increased upregulation of transmembrane serine proteases (TTSPs) leads to an overactivation of growth factors, which promotes tumor progression. Here, we have used a combinatorial methodology to develop high-affinity tetrapeptidic inhibitors. A previous virtual screening of 8000 peptide combinations against the crystal structure of the TTSP hepsin identified a series of recognition sequences, customized for the non-prime substrate binding (P) sites of this serine protease. A combination of the top recognition sequences with an electrophilic warhead resulted in highly potent inhibitors with good selectivity against coagulation proteases factor Xa and thrombin. Structure-activity relationships of two selected compounds were further elucidated by investigation of their stability in biological fluids as well as the influence of the warhead and truncated inhibitors on the inhibitory potency. Overall, this methodology yielded compounds as selective inhibitors for potential cancer drug development, where hepsin is overexpressed.
Autoren
  • Philip Maximilian Knaff
  • Patrick Müller
  • Christian Kersten
  • Lukas Wettstein
  • Jan Münch
  • Katharina Landfester
  • Volker Mailänder
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/35593713
DOI
10.1021/acs.biomac.1c01011
eISSN
1526-4602
Ausgabe der Veröffentlichung
6
Zeitschrift
Biomacromolecules
Schlüsselwörter
  • Drug Design
  • Peptidomimetics
  • Serine Endopeptidases
  • Serine Proteases
  • Serine Proteinase Inhibitors
  • Structure-Activity Relationship
Sprache
eng
Country
United States
Paginierung
2236 - 2242
Datum der Veröffentlichung
2022
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2022
Titel
Structure-Based Design of High-Affinity and Selective Peptidomimetic Hepsin Inhibitors.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
23

Datenquelle: PubMed

Beziehungen:
Eigentum von

Werkzeuge