Chemoproteomics-Enabled Identification of 4-Oxo-β-Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9.
Chemoproteomics-Enabled Identification of 4-Oxo-β-Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9.
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DOI：
10.1002/anie.202210498
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发表时间：
2022-11-21
影响因子：
16.6
通讯作者：
Moreira, Rui
中科院分区：
文献类型：
--
作者：
Carvalho, Luis A. R.;Ross, Breyan;Fehr, Lorenz;Bolgi, Oguz;Woehrle, Svenja;Lum, Kenneth M.;Podlesainski, David;Vieira, Andreia C.;Kiefersauer, Reiner;Felix, Rita;Rodrigues, Tiago;Lucas, Susana D.;Gross, Olaf;Geiss-Friedlander, Ruth;Cravatt, Benjamin F.;Huber, Robert;Kaiser, Markus;Moreira, Rui
关键词：
二肽基肽酶8和9（DPP 8/9）由于其在免疫和肿瘤发生等生物学过程中的重要作用而作为药物靶点引起了人们的兴趣。阐明其独特的个人功能仍然是一个持续的任务，并可能受益于新的，化学多样性和选择性的化学工具的可用性。在这里，我们报告了基于活性的蛋白质谱（ABPP）介导的4-氧代-β-内酰胺作为有效的非底物样纳摩尔DPP 8/9抑制剂的发现。X射线晶体结构揭示了DPP 8和DPP 9的不同配体结合模式，包括DPP 8中扩展的S2′（eS 2 ′）亚位点的前所未有的靶向。生物测定证实了在靶和细胞水平上的抑制。总而言之，我们的综合化学蛋白质组学和结构指导的小分子设计方法导致了具有替代分子抑制机制的新型DPP 8/9抑制剂，提供了迄今为止报道的最高选择性指数。实现二肽基肽酶8和9（DPP 8/9）的选择性是化学生物学中的当前挑战。在基于活性的蛋白质分析和X射线晶体学的支持下，我们公开了4-氧代-β-内酰胺作为有效的非底物样纳摩尔DPP 8/9抑制剂，具有不同的DPP 8/9结合模式，包括前所未有的DPP 8中扩展的S2′亚位点靶向和迄今为止报道的最佳选择性指数。
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‐β‐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. Achieving Dipeptidyl Peptidase 8 and 9 (DPP8/9) selectivity is a current challenge in chemical biology. Supported by activity‐based protein profiling and X‐ray crystallography, we disclose 4‐oxo‐β‐lactams as potent, non‐substrate‐like nanomolar DPP8/9 inhibitors with different binding modes for DPP8/9, including an unprecedented targeting of an extended S2′ subsite in DPP8 and the best selectivity index reported to date.
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影响因子：
--
作者：
Heirbaut, Leen;van Goethem, Sebastiaan;van der Veken, Pieter
通讯作者：
van der Veken, Pieter
影响因子：
7.7
作者：
Justa-Schuch, Daniela;Silva-Garcia, Maria;Geiss-Friedlander, Ruth
通讯作者：
Geiss-Friedlander, Ruth
DOI：
10.1046/j.1432-1327.2000.01617.x
发表时间：
2000-10-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Abbott, CA;Yu, DMT;Gorrell, MD
通讯作者：
Gorrell, MD
影响因子：
64.8
作者：
Hollingsworth LR;Sharif H;Griswold AR;Fontana P;Mintseris J;Dagbay KB;Paulo JA;Gygi SP;Bachovchin DA;Wu H
通讯作者：
Wu H
影响因子：
7.3
作者：
Irwin JJ;Duan D;Torosyan H;Doak AK;Ziebart KT;Sterling T;Tumanian G;Shoichet BK
通讯作者：
Shoichet BK