Sewald Leonard, Tabak Werner W A, Fehr Lorenz, Zolg Samuel, Najdzion Maja, Verhoef Carlo J A, Podlesainski David, Geiss-Friedlander Ruth, Lammens Alfred, Kaschani Farnusch, Hellerschmied Doris, Huber Robert, Kaiser Markus
Chemical Biology, Center of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Essen, Germany.
Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Nat Commun. 2025 Apr 3;16(1):3208. doi: 10.1038/s41467-025-58493-z.
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.
共价化学探针和药物将独特的药理特性与通过化学蛋白质组学平台进行直接化合物分析技术的可用性相结合。这些优势推动了用于系统共价化学探针发现的合适亲电“弹头”的开发。尽管在过去几年中取得了无可争议的进展，但针对蛋白质组范围的选择性共价探针的开发对于二肽基肽酶（DPP）8和9（DPP8/9）——药理学相关的二肽基肽酶4活性/结构同源物（DASH）家族的细胞内丝氨酸水解酶——来说仍然是一个挑战。在此，我们展示了对天然产物磺抑素（一种DPP4抑制剂）的探索，作为DPP8/9抑制剂开发的起点。受磺抑素启发的N-膦酰基哌啶酮的产生导致了具有改善的DPP8/9抑制效力、增强的蛋白质组范围选择性以及在细胞中确认的DPP8/9结合的衍生物，从而表明弹头离去基团的结构微调可能是在外肽酶如DPPs中实现目标选择性的直接策略。
