Investigation of the compatibility between warheads and peptidomimetic sequences of protease inhibitors — a comprehensive reactivity and selectivity study
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- Covalent peptidomimetic protease inhibitors have gained a lot of attention in drug development in recent years. They are designed to covalently bind the catalytically active amino acids through electrophilic groups called warheads. Covalent inhibition has an advantage in terms of pharmacodynamic properties but can also bear toxicity risks due to non-selective off-target protein binding. Therefore, the right combination of a reactive warhead with a well-suited peptidomimetic sequence is of great importance. Herein, the selectivities ofCovalent peptidomimetic protease inhibitors have gained a lot of attention in drug development in recent years. They are designed to covalently bind the catalytically active amino acids through electrophilic groups called warheads. Covalent inhibition has an advantage in terms of pharmacodynamic properties but can also bear toxicity risks due to non-selective off-target protein binding. Therefore, the right combination of a reactive warhead with a well-suited peptidomimetic sequence is of great importance. Herein, the selectivities of well-known warheads combined with peptidomimetic sequences suited for five different proteases were investigated, highlighting the impact of both structure parts (warhead and peptidomimetic sequence) for affinity and selectivity. Molecular docking gave insights into the predicted binding modes of the inhibitors inside the binding pockets of the different enzymes. Moreover, the warheads were investigated by NMR and LC-MS reactivity assays against serine/threonine and cysteine nucleophile models, as well as by quantum mechanics simulations.…
Autor(en): | Patrick Müller, Mergim Meta, Jan Laurenz Meidner, Marvin Schwickert, Jessica Meyr, Kevin Schwickert, Christian Kersten, Collin Zimmer, Stefan Josef Hammerschmidt, Ariane Frey, Albin Lahu, Sergio de la Hoz-Rodríguez, Laura Agost-Beltrán, Santiago Rodríguez, Kira Diemer, Wilhelm Neumann, Florenci V. Gonzàlez, Bernd Engels, Tanja Schirmeister |
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URN: | urn:nbn:de:bvb:20-opus-313596 |
Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
Institute der Universität: | Fakultät für Chemie und Pharmazie / Institut für Physikalische und Theoretische Chemie |
Sprache der Veröffentlichung: | Englisch |
Titel des übergeordneten Werkes / der Zeitschrift (Englisch): | International Journal of Molecular Sciences |
ISSN: | 1422-0067 |
Erscheinungsjahr: | 2023 |
Band / Jahrgang: | 24 |
Heft / Ausgabe: | 8 |
Aufsatznummer: | 7226 |
Originalveröffentlichung / Quelle: | International Journal of Molecular Sciences (2023) 24:8, 7226. https://doi.org/10.3390/ijms24087226 |
DOI: | https://doi.org/10.3390/ijms24087226 |
Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften |
Freie Schlagwort(e): | covalent inhibitors; in vitro study; peptidomimetic sequence; protease inhibitors; reactivity and selectivity study; warhead |
Datum der Freischaltung: | 04.12.2023 |
Datum der Erstveröffentlichung: | 13.04.2023 |
Lizenz (Deutsch): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |