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  - 
TY  - JOUR
A1  - Geiger, Nina
A1  - Diesendorf, Viktoria
A1  - Roll, Valeria
A1  - König, Eva-Maria
A1  - Obernolte, Helena
A1  - Sewald, Katherina
A1  - Breidenbach, Julian
A1  - Pillaiyar, Thanigaimalai
A1  - Gütschow, Michael
A1  - Müller, Christa E.
A1  - Bodem, Jochen
T1  - Cell type-specific anti-viral effects of novel SARS-CoV-2 main protease inhibitors
JF  - International Journal of Molecular Sciences
N2  - Recently, we have described novel pyridyl indole esters and peptidomimetics as potent inhibitors of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) main protease. Here, we analysed the impact of these compounds on viral replication. It has been shown that some antivirals against SARS-CoV-2 act in a cell line-specific way. Thus, the compounds were tested in Vero, Huh-7, and Calu-3 cells. We showed that the protease inhibitors at 30 µM suppress viral replication by up to 5 orders of magnitude in Huh-7 cells, while in Calu-3 cells, suppression by 2 orders of magnitude was achieved. Three pyridin-3-yl indole-carboxylates inhibited viral replication in all cell lines, indicating that they might repress viral replication in human tissue as well. Thus, we investigated three compounds in human precision-cut lung slices and observed donor-dependent antiviral activity in this patient-near system. Our results provide evidence that even direct-acting antivirals may act in a cell line-specific manner.
KW  - SARS-CoV-2
KW  - protease inhibitors
KW  - cell line specificity pyridyl indole carboxylates
KW  - azapeptide nitriles
KW  - peptidomimetics
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304034
SN  - 1422-0067
VL  - 24
IS  - 4
ER  -