4.8 Article

Chemoproteomics-Enabled Identification of 4-Oxo-β-Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9

期刊

出版社

WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202210498

关键词

Activity-Based Protein Profiling; Dipeptidyl Peptidases 8/9; 4-Oxo-beta-Lactams; Proteomics; X-Ray Diffraction

资金

  1. Fundacao para a Ciencia e a Tecnologia (FCT, Portugal) [PTDC/MEDCAR/31322/2017, SAICTPAC/0019/2015, PTDC/MEDQUI/30021/2017, UIDB/04138/2020, UIDP/04138/2020, SFRH/BD/100400/2014, SFRH/BD/137459/2018]
  2. European Union [LISBOA-01-0145-FEDER-016405]
  3. FCT
  4. Deutsche Forschungsgemeinschaft (DFG) [2234/1-3]
  5. DFG [GRK2606, 423813989]
  6. Peter and Traudl Engelhorn Stiftung
  7. Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [423813989, SFB 1160, 256073931, SFB/TRR 167, 259373024, SFB 1425, 422681845, SFB 1479, 441891347, GRK 2606, 390939984, EXC-2189]
  8. European Research Council (ERC) [966687, 101034170]
  9. Deutsche Forschungsgemeinschaft [SFB1430]
  10. NIH [R35 CA231991]
  11. European Research Council (ERC) [966687] Funding Source: European Research Council (ERC)

向作者/读者索取更多资源

Dipeptidyl peptidases 8 and 9 (DPP8/9) have important roles in biological processes and are potential drug targets. This study discovered 4-oxo-beta-lactams as potent DPP8/9 inhibitors using activity-based protein profiling. X-ray crystallography revealed different ligand binding modes for DPP8 and DPP9. The inhibitors showed inhibition at both the target and cellular levels, with the highest reported selectivity index.
Dipeptidyl peptidases 8 and 9 (DPP8/9) have gathered interest as drug targets due to their important roles in biological processes like immunity and tumorigenesis. Elucidation of their distinct individual functions remains an ongoing task and could benefit from the availability of novel, chemically diverse and selective chemical tools. Here, we report the activity-based protein profiling (ABPP)-mediated discovery of 4-oxo-beta-lactams as potent, non-substrate-like nanomolar DPP8/9 inhibitors. X-ray crystallographic structures revealed different ligand binding modes for DPP8 and DPP9, including an unprecedented targeting of an extended S2' (eS2') subsite in DPP8. Biological assays confirmed inhibition at both target and cellular levels. Altogether, our integrated chemical proteomics and structure-guided small molecule design approach led to novel DPP8/9 inhibitors with alternative molecular inhibition mechanisms, delivering the highest selectivity index reported to date.

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