Synthesis of Novel Phosphonic‐Type Activity‐Based Probes for Neutrophil Serine Proteases and Their Application in Spleen Lysates of Different Organisms |
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| Authors: | Dr Renata Grzywa Dr Ewa Burchacka Maria ??cka Dr ?ukasz Winiarski Maciej Walczak Agnieszka ?upicka‐S?owik Dr Magdalena Wysocka Prof Timo Burster Dr Kamila Bobrek Dr Keri Csencsits‐Smith Prof Adam Lesner Dr Marcin Sieńczyk |
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| Affiliation: | 1. Division Of Medicinal Chemistry and Microbiology, Faculty of Chemistry, Wroclaw University of Technology, Wybrze?e Wyspiańskiego 27, 50‐370 Wroclaw (Poland);2. Division of Biochemistry, Faculty of Chemistry, Gdańsk University, Sobieskiego 18, 80‐952 Gdansk (Poland);3. Department of Neurosurgery, Ulm University Medical Centre, Albert‐Einstein‐Allee 23, 89081 Ulm (Germany);4. Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53‐114 Wroc?aw (Poland);5. Faculty of Veterinary Medicine, Department of Immunology, Pathophysiology and Veterinary Preventive Medicine, Wroclaw University of Environmental and Life Sciences, Norwida 31, 50‐375 Wroclaw (Poland);6. Department of Pathology and Laboratory Medicine, University of Texas–Houston Medical School, 6431 Fannin Street, Houston, Texas 77030 (USA) |
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| Abstract: | Neutrophils are a type of granulocyte important in the “first line of defense” of the innate immune system. Upon activation, they facilitate the destruction of invading microorganisms by the production of superoxide radicals, as well as the release of the enzymatic contents of their lysozymes. These enzymes include specific serine proteases: cathepsin G, neutrophil elastase, proteinase 3, as well as the recently discovered neutrophil serine protease 4 (NSP4). Under normal conditions, the proteolytic activity of neutrophil proteases is tightly regulated by endogenous serpins; however, this mechanism can be subverted during tissue stress, thereby resulting in the uncontrolled activity of serine proteases, which induce chronic inflammation and subsequent pathology. Herein, we describe the development of low‐molecular‐weight activity‐based probes that specifically target the active sites of neutrophil proteases. |
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| Keywords: | activity‐based probes aminophosphonates inhibitors neutrophil serine proteases peptidomimetics |
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