Aryl Fluorosulfate Based Inhibitors That Covalently Target the SIRT5 Lysine Deacylase**

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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.

OriginalsprogEngelsk
Artikelnummere202204565
TidsskriftAngewandte Chemie - International Edition
Vol/bind61
Udgave nummer47
Antal sider11
ISSN1433-7851
DOI
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
We thank M. Bæk and A. L. Nielsen for assistance with pull‐down, overexpression, and donation of reagents. We thank S. A. Pless for donation of HEK293T cells as well as insightful comments on the manuscript and J. Kritzer for providing the HaloTag‐expressing HeLa cell line. We thank H. S. Larsen and M. Caldara for animal facility assistance and Samuel A. J. Trammell for insightful information on peptide mass fingerprinting. The SIRT5‐Flag vector was a gift from E. Verdin (Addgene plasmid #13816). We gratefully acknowledge financial support from the Carlsberg Foundation (2013‐01‐033 and CF15‐0115, C.A.O.), the Novo Nordisk Foundation (NNF17OC0029464, C.A.O.; NNF13OC0004294, M.J.D.), the Lundbeck Foundation (R289‐2018‐2074, C.A.O.; R322‐2019‐2337, L.F.G.), and the Independent Research Fund Denmark‐Medical Sciences (0134‐00435B; C.A.O.). This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement number: CoG‐725172 “; C.A.O.). SIRFUNCT”

Publisher Copyright:
© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.

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