TY  - JOUR
A1  - Müller, Patrick
A1  - Meta, Mergim
A1  - Meidner, Jan Laurenz
A1  - Schwickert, Marvin
A1  - Meyr, Jessica
A1  - Schwickert, Kevin
A1  - Kersten, Christian
A1  - Zimmer, Collin
A1  - Hammerschmidt, Stefan Josef
A1  - Frey, Ariane
A1  - Lahu, Albin
A1  - de la Hoz-Rodríguez, Sergio
A1  - Agost-Beltrán, Laura
A1  - Rodríguez, Santiago
A1  - Diemer, Kira
A1  - Neumann, Wilhelm
A1  - Gonzàlez, Florenci V.
A1  - Engels, Bernd
A1  - Schirmeister, Tanja
T1  - Investigation of the compatibility between warheads and peptidomimetic sequences of protease inhibitors — a comprehensive reactivity and selectivity study
JF  - International Journal of Molecular Sciences
N2  - 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 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.
KW  - covalent inhibitors
KW  - in vitro study
KW  - protease inhibitors
KW  - peptidomimetic sequence
KW  - warhead
KW  - reactivity and selectivity study
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313596
SN  - 1422-0067
VL  - 24
IS  - 8
ER  -