Publication
Title
Active site-directed probes targeting dipeptidyl peptidases 8 and 9
Author
Abstract
Dipeptidyl peptidases (DPP) 8 and 9 are intracellular serine proteases that play key roles in various biological processes and recent findings highlight DPP8 and DPP9 as potential therapeutic targets for hematological and inflammasome-related diseases. Despite the substantial progress, the precise biological functions of these proteases remain elusive, and the lack of selective chemical tools hampers ongoing research. In this paper, we describe the synthesis and biochemical evaluation of the first active site-directed DPP8/9 probes which are derived from DPP8/9 inhibitors developed in-house. Specifically, we synthesized fluorescent inhibitors containing nitrobenzoxadiazole (NBD), dansyl (DNS) and cyanine-3 (Cy3) reporters to visualize intracellular DPP8/9. We demonstrate that the fluorescent inhibitors have high affinity and selectivity towards DPP8/9 over related S9 family members. The NBD-labeled DPP8/9 inhibitors were nominated as the best in class compounds to visualize DPP8/9 in human cells. Furthermore, a method has been developed for selective labeling and visualization of active DPP8/9 in vitro by fluorescence microscopy. A collection of potent and selective biotinylated DPP8/9-targeting probes was also prepared by replacing the fluorescent reporter with a biotin group. The present work provides the first DPP8/9-targeting fluorescent compounds as useful chemical tools for the study of DPP8 and DPP9's biological functions.
Language
English
Source (journal)
European journal of medicinal chemistry. - Paris, 1974, currens
Publication
Paris : 2024
ISSN
0223-5234
DOI
10.1016/J.EJMECH.2024.116389
Volume/pages
270 (2024) , p. 1-12
Article Reference
116389
ISI
001225540100001
Pubmed ID
38593588
Full text (Publisher's DOI)
Full text (open access)
The author-created version that incorporates referee comments and is the accepted for publication version Available from 08.10.2024
Full text (publisher's version - intranet only)
UAntwerpen
Faculty/Department
Research group
Project info
The role of dipeptidyl peptidase 9 (DPP9) in human monocyte-derived macrophages: Discovery of DPP9 binding partners & natural substrates using novel chemical and cellular tools.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Record
Identifier
Creation 09.04.2024
Last edited 28.05.2024
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