Design and synthesis of tailored human caseinolytic protease P inhibitors

被引：23

作者：

Gronauer, Thomas F. ^{[1
]}

Mandl, Melanie M. ^{[3
]}

Lakemeyer, Markus ^{[1
]}

Hackl, Mathias W. ^{[1
]}

Messner, Martina ^{[2
]}

Korotkov, Vadim S. ^{[1
]}

Pachmayr, Johanna ^{[2
]}

Sieber, Stephan A. ^{[1
]}

机构：

[1] Tech Univ Munich, Dept Chem, Ctr Integrated Prot Sci Munich, Lichtenbergstr 4, D-85748 Garching, Germany

[2] Paracelsus Med Privatuniv Salzburg, Strubergasse 21, A-5020 Salzburg, Austria

[3] Ludwig Maximilians Univ Munich LMU, Dept Pharm, Pharmaceut Biol, Butenandtstr 5-13, D-81377 Munich, Germany

来源：

CHEMICAL COMMUNICATIONS | 2018年 / 54卷 / 70期

关键词：

STAPHYLOCOCCUS-AUREUS; TERMINAL ALKYNES; CLPP; MITOCHONDRIA; ACCUMULATION; ACTIVATION; MECHANISM; LEUKEMIA; MACHINE; ELEGANS;

D O I：

10.1039/c8cc05265d

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Human caseinolytic protease P (hClpP) is important for degradation of misfolded proteins in the mitochondrial unfolded protein response. We here introduce tailored hClpP inhibitors that utilize a steric discrimination in their core naphthofuran scaffold to selectively address the human enzyme. This novel inhibitor generation exhibited superior activity compared to previously introduced betalactones, optimized for bacterial ClpP. Further insights into the bioactivity and binding to cellular targets were obtained via chemical proteomics as well as proliferation- and migration studies in cancer cells.

引用

页码：9833 / 9836

页数：4

共 30 条

[1] The Role of ClpP Protease in Bacterial Pathogenesis and Human Diseases [J].

Bhandari, Vaibhav ;

Wong, Keith S. ;

Zhou, Jin Lin ;

Mabanglo, Mark F. ;

Batey, Robert A. ;

Houry, Walid A. .

ACS CHEMICAL BIOLOGY, 2018, 13 (06) :1413-1425

[2] β-Lactones as Specific Inhibitors of CIpP Attenuate the Production of Extracellular Virulence Factors of Staphylococcus aureus [J].

Boettcher, Thomas ;

Sieber, Stephan A. .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2008, 130 (44) :14400-+

[3] Dysregulation of bacterial proteolytic machinery by a new class of antibiotics [J].

Brötz-Oesterhelt, H ;

Beyer, D ;

Kroll, HP ;

Endermann, R ;

Ladel, C ;

Schroeder, W ;

Hinzen, B ;

Raddatz, S ;

Paulsen, H ;

Henninger, K ;

Bandow, JE ;

Sahl, HG ;

Labischinski, H .

NATURE MEDICINE, 2005, 11 (10) :1082-1087

[4] A Simple Fragment of Cyclic Acyldepsipeptides Is Necessary and Sufficient for ClpP Activation and Antibacterial Activity [J].

Carney, Daniel W. ;

Compton, Corey L. ;

Schmitz, Karl R. ;

Stevens, Julia P. ;

Sauer, Robert T. ;

Sello, Jason K. .

CHEMBIOCHEM, 2014, 15 (15) :2216-2220

[5] Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia [J].

Cole, Alicia ;

Wang, Zezhou ;

Coyaud, Etienne ;

Voisin, Veronique ;

Gronda, Marcela ;

Jitkova, Yulia ;

Mattson, Rachel ;

Hurren, Rose ;

Babovic, Sonja ;

Maclean, Neil ;

Restall, Ian ;

Wang, Xiaoming ;

Jeyaraju, Danny V. ;

Sukhai, Mahadeo A. ;

Prabha, Swayam ;

Bashir, Shaheena ;

Ramakrishnan, Ashwin ;

Leung, Elisa ;

Qia, Yi Hua ;

Zhang, Nianxian ;

Combes, Kevin R. ;

Ketela, Troy ;

Lin, Fengshu ;

Houry, Walid A. ;

Aman, Ahmed ;

Al-awar, Rima ;

Zheng, Wei ;

Wienholds, Erno ;

Xu, Chang Jiang ;

Dick, John ;

Wang, Jean C. Y. ;

Moffat, Jason ;

Minden, Mark D. ;

Eaves, Connie J. ;

Bader, Gary D. ;

Hao, Zhenyue ;

Kornblau, Steven M. ;

Raught, Brian ;

Schimmer, Aaron D. .

CANCER CELL, 2015, 27 (06) :864-876

[6] AEG-1/MTDH/LYRIC: A Promiscuous Protein Partner Critical in Cancer, Obesity, and CNS Diseases [J].

Emdad, L. ;

Das, S. K. ;

Hu, B. ;

Kegelman, T. ;

Kang, D. -C. ;

Lee, S. -G. ;

Sarkar, D. ;

Fisher, P. B. .

ADVANCES IN CANCER RESEARCH, VOL 131, 2016, 131 :97-132

[7] Mechanism-based profiling of enzyme families [J].

Evans, Michael J. ;

Cravatt, Benjamin F. .

CHEMICAL REVIEWS, 2006, 106 (08) :3279-3301

[8] Activity-based probes as a tool for functional proteomic analysis of proteases [J].

Fonovic, Marko ;

Bogyo, Matthew .

EXPERT REVIEW OF PROTEOMICS, 2008, 5 (05) :721-730

[9] The Mechanism of Caseinolytic Protease (ClpP) Inhibition [J].

Gersch, Malte ;

Gut, Felix ;

Korotkov, Vadim S. ;

Lehmann, Johannes ;

Boettcher, Thomas ;

Rusch, Marion ;

Hedberg, Christian ;

Waldmann, Herbert ;

Klebe, Gerhard ;

Sieber, Stephan A. .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2013, 52 (10) :3009-3014

[10] Mitochondrial Proteases as Emerging Pharmacological Targets [J].

Gibellini, Lara ;

De Biasi, Sara ;

Nasi, Milena ;

Iannone, Anna ;

Cossarizza, Andrea ;

Pinti, Marcello .

CURRENT PHARMACEUTICAL DESIGN, 2016, 22 (18) :2679-2688

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