Aryl Fluorosulfate Based Inhibitors That Covalently Target the SIRT5 Lysine Deacylase**
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Aryl Fluorosulfate Based Inhibitors That Covalently Target the SIRT5 Lysine Deacylase**. / Bolding, Julie E.; Martín-Gago, Pablo; Rajabi, Nima; Gamon, Luke F.; Hansen, Tobias N.; Bartling, Christian R.O.; Strømgaard, Kristian; Davies, Michael J.; Olsen, Christian A.
In: Angewandte Chemie - International Edition, Vol. 61, No. 47, e202204565, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Aryl Fluorosulfate Based Inhibitors That Covalently Target the SIRT5 Lysine Deacylase**
AU - Bolding, Julie E.
AU - Martín-Gago, Pablo
AU - Rajabi, Nima
AU - Gamon, Luke F.
AU - Hansen, Tobias N.
AU - Bartling, Christian R.O.
AU - Strømgaard, Kristian
AU - Davies, Michael J.
AU - Olsen, Christian A.
N1 - Publisher Copyright: © 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.
PY - 2022
Y1 - 2022
N2 - The sirtuin enzymes are a family of lysine deacylases that regulate gene transcription and metabolism. Sirtuin 5 (SIRT5) hydrolyzes malonyl, succinyl, and glutaryl ϵ-N-carboxyacyllysine posttranslational modifications and has recently emerged as a vulnerability in certain cancers. However, chemical probes to illuminate its potential as a pharmacological target have been lacking. Here we report the harnessing of aryl fluorosulfate-based electrophiles as an avenue to furnish covalent inhibitors that target SIRT5. Alkyne-tagged affinity-labeling agents recognize and capture overexpressed SIRT5 in cultured HEK293T cells and can label SIRT5 in the hearts of mice upon intravenous injection of the compound. This work demonstrates the utility of aryl fluorosulfate electrophiles for targeting of SIRT5 and suggests this as a means for the development of potential covalent drug candidates. It is our hope that these results will serve as inspiration for future studies investigating SIRT5 and general sirtuin biology in the mitochondria.
AB - The sirtuin enzymes are a family of lysine deacylases that regulate gene transcription and metabolism. Sirtuin 5 (SIRT5) hydrolyzes malonyl, succinyl, and glutaryl ϵ-N-carboxyacyllysine posttranslational modifications and has recently emerged as a vulnerability in certain cancers. However, chemical probes to illuminate its potential as a pharmacological target have been lacking. Here we report the harnessing of aryl fluorosulfate-based electrophiles as an avenue to furnish covalent inhibitors that target SIRT5. Alkyne-tagged affinity-labeling agents recognize and capture overexpressed SIRT5 in cultured HEK293T cells and can label SIRT5 in the hearts of mice upon intravenous injection of the compound. This work demonstrates the utility of aryl fluorosulfate electrophiles for targeting of SIRT5 and suggests this as a means for the development of potential covalent drug candidates. It is our hope that these results will serve as inspiration for future studies investigating SIRT5 and general sirtuin biology in the mitochondria.
KW - Covalent Inhibition
KW - Enzyme Inhibitors
KW - SIRT5
KW - Sirtuins
KW - SuFEx
U2 - 10.1002/anie.202204565
DO - 10.1002/anie.202204565
M3 - Journal article
C2 - 36130196
AN - SCOPUS:85140261083
VL - 61
JO - Angewandte Chemie International Edition
JF - Angewandte Chemie International Edition
SN - 1433-7851
IS - 47
M1 - e202204565
ER -
ID: 324592435