Validation of the Slow Off-Kinetics of Sirtuin-Rearranging Ligands (SirReals) by Means of Label-Free Electrically Switchable Nanolever Technology
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Validation of the Slow Off-Kinetics of Sirtuin-Rearranging Ligands (SirReals) by Means of Label-Free Electrically Switchable Nanolever Technology. / Schiedel, Matthias; Daub, Herwin; Itzen, Aymelt; Jung, Manfred.
In: CHEMBIOCHEM, Vol. 21, No. 8, 17.04.2020, p. 1161-1166.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Validation of the Slow Off-Kinetics of Sirtuin-Rearranging Ligands (SirReals) by Means of Label-Free Electrically Switchable Nanolever Technology
AU - Schiedel, Matthias
AU - Daub, Herwin
AU - Itzen, Aymelt
AU - Jung, Manfred
N1 - © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
PY - 2020/4/17
Y1 - 2020/4/17
N2 - We have discovered the sirtuin-rearranging ligands (SirReals) to be highly potent and selective inhibitors of the NAD+ -dependent lysine deacetylase Sirt2. Using a biotinylated SirReal in combination with biolayer interferometry, we previously observed a slow dissociation rate of the inhibitor-enzyme complex; this had been postulated to be the key to the high affinity and selectivity of SirReals. However, to attach biotin to the SirReal core, we introduced a triazole as a linking moiety; this was shown by X-ray co-crystallography to interact with Arg97 of the cofactor binding loop. Herein, we aim to elucidate whether the observed long residence time of the SirReals is induced mainly by triazole incorporation or is an inherent characteristic of the SirReal inhibitor core. We used the novel label-free switchSENSE® technology, which is based on electrically switchable DNA nanolevers, to prove that the long residence time of the SirReals is indeed caused by the core scaffold.
AB - We have discovered the sirtuin-rearranging ligands (SirReals) to be highly potent and selective inhibitors of the NAD+ -dependent lysine deacetylase Sirt2. Using a biotinylated SirReal in combination with biolayer interferometry, we previously observed a slow dissociation rate of the inhibitor-enzyme complex; this had been postulated to be the key to the high affinity and selectivity of SirReals. However, to attach biotin to the SirReal core, we introduced a triazole as a linking moiety; this was shown by X-ray co-crystallography to interact with Arg97 of the cofactor binding loop. Herein, we aim to elucidate whether the observed long residence time of the SirReals is induced mainly by triazole incorporation or is an inherent characteristic of the SirReal inhibitor core. We used the novel label-free switchSENSE® technology, which is based on electrically switchable DNA nanolevers, to prove that the long residence time of the SirReals is indeed caused by the core scaffold.
U2 - 10.1002/cbic.201900527
DO - 10.1002/cbic.201900527
M3 - SCORING: Journal article
C2 - 31692222
VL - 21
SP - 1161
EP - 1166
JO - CHEMBIOCHEM
JF - CHEMBIOCHEM
SN - 1439-4227
IS - 8
ER -
