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Sulphostin-inspired N-phosphonopiperidones as selective covalent DPP8 and DPP9 inhibitors
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Sulphostin-inspired N-phosphonopiperidones as selective covalent DPP8 and DPP9 inhibitors
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Journal Article
Sulphostin-inspired N-phosphonopiperidones as selective covalent DPP8 and DPP9 inhibitors
2025
Overview
Covalent chemical probes and drugs combine unique pharmacologic properties with the availability of straightforward compound profiling technologies via chemoproteomic platforms. These advantages have fostered the development of suitable electrophilic “warheads” for systematic covalent chemical probe discovery. Despite undisputable advances in the last years, the targeted development of proteome-wide selective covalent probes remains a challenge for dipeptidyl peptidase (DPP) 8 and 9 (DPP8/9), intracellular serine hydrolases of the pharmacologically relevant dipeptidyl peptidase 4 activity/structure homologues (DASH) family. Here, we show the exploration of the natural product Sulphostin, a DPP4 inhibitor, as a starting point for DPP8/9 inhibitor development. The generation of Sulphostin-inspired
N
-phosphonopiperidones leads to derivatives with improved DPP8/9 inhibitory potency, an enhanced proteome-wide selectivity and confirmed DPP8/9 engagement in cells, thereby representing that structural fine-tuning of the warhead’s leaving group may represent a straightforward strategy for achieving target selectivity in exoproteases such as DPPs.
The targeted development of proteome-wide selective covalent probes remains a challenge. Here, the authors show the exploration of the natural product Sulphostin as a starting point for dipeptidyl peptidase 8 and 9 inhibitor development.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Dipeptidases - antagonists & inhibitors
/ Dipeptidyl Peptidase 4 - metabolism
/ Dipeptidyl-Peptidase IV Inhibitors - chemistry
/ Dipeptidyl-Peptidase IV Inhibitors - pharmacology
/ Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - antagonists & inhibitors
/ Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - metabolism
/ Humanities and Social Sciences
/ Humans
/ Probes
/ Science
/ Structure-Activity Relationship
/ Warheads
