TY  - JOUR
A1  - Welker, Armin
A1  - Kersten, Christian
A1  - Müller, Christin
A1  - Madhugiri, Ramakanth
A1  - Zimmer, Collin
A1  - Müller, Patrick
A1  - Zimmermann, Robert
A1  - Hammerschmidt, Stefan
A1  - Maus, Hannah
A1  - Ziebuhr, John
A1  - Sotriffer, Christoph
A1  - Schirmeister, Tanja
T1  - Structure‐Activity Relationships of Benzamides and Isoindolines Designed as SARS‐CoV Protease Inhibitors Effective against SARS‐CoV‐2
JF  - ChemMedChem
N2  - Inhibition of coronavirus (CoV)‐encoded papain‐like cysteine proteases (PL\(^{pro}\)) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure‐activity relationships (SAR) of the noncovalent active‐site directed inhibitor (R)‐5‐amino‐2‐methyl‐N‐(1‐(naphthalen‐1‐yl)ethyl) benzamide (2 b), which is known to bind into the S3 and S4 pockets of the SARS‐CoV PL\(^{pro}\). Moreover, we report the discovery of isoindolines as a new class of potent PL\(^{pro}\) inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS‐CoV‐2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS‐CoV PL\(^{pro}\) are valuable starting points for the development of new pan‐coronaviral inhibitors.
KW  - antiviral agents
KW  - computational chemistry
KW  - drug design
KW  - protease inhibitors
KW  - structure-activity relationships
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225700
VL  - 16
IS  - 2
SP  - 340
EP  - 354
ER  - 
TY  - JOUR
A1  - Dirimanov, Stoyan
A1  - Högger, Petra
T1  - Screening of inhibitory effects of polyphenols on Akt-phosphorylation in endothelial cells and determination of structure-activity features
JF  - Biomolecules
N2  - Polyphenols exert beneficial effects in type 2 diabetes mellitus (T2DM). However, their mechanism of action remains largely unknown. Endothelial Akt-kinase plays a key role in the pathogenesis of cardiovascular complications in T2DM and therefore the modulation of its activity is of interest. This work aimed to characterize effects of structurally different polyphenols on Akt-phosphorylation (pAkt) in endothelial cells (Ea.hy926) and to describe structure-activity features. A comprehensive screening via ELISA quantified the effects of 44 polyphenols (10 µM) on pAkt Ser473. The most pronounced inhibitors were luteolin (44 ± 18%), quercetin (36 ± 8%), urolithin A (35 ± 12%), apigenin, fisetin, and resveratrol; (p < 0.01). The results were confirmed by Western blotting and complemented with corresponding experiments in HUVEC cells. A strong positive and statistically significant correlation between the mean inhibitory effects of the tested polyphenols on both Akt-residues Ser473 and Thr308 (r = 0.9478, p = 0.0003) was determined by immunoblotting. Interestingly, the structural characteristics favoring pAkt inhibition partially differed from structural features enhancing the compounds’ antioxidant activity. The present study is the first to quantitatively compare the influence of polyphenols from nine different structural subclasses on pAkt in endothelial cells. These effects might be advantageous in certain T2DM-complications involving over-activation of the Akt-pathway. The suggested molecular mode of action of polyphenols involving Akt-inhibition contributes to understanding their effects on the cellular level.
KW  - Akt/PKB
KW  - endothelium
KW  - diabetes
KW  - polyphenols
KW  - in vitro
KW  - structure-activity relationships
KW  - screening
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197333
SN  - 2218-273X
VL  - 9
IS  - 6
ER  -