5a09
From Proteopedia
Crystal Structure of human neutrophil elastase in complex with a dihydropyrimidone inhibitor
Structural highlights
Disease[ELNE_HUMAN] Defects in ELANE are a cause of cyclic haematopoiesis (CH) [MIM:162800]; also known as cyclic neutropenia. CH is an autosomal dominant disease in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes and reticulocytes also cycle with the same frequency.[1] [2] Defects in ELANE are the cause of neutropenia severe congenital autosomal dominant type 1 (SCN1) [MIM:202700]. SCN1 is a disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections.[3] Function[ELNE_HUMAN] Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis.[4] Publication Abstract from PubMedHuman neutrophil elastase (HNE) is a key protease for matrix degradation. High HNE activity is observed in inflammatory diseases. Accordingly, HNE is a potential target for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), bronchiectasis (BE), and pulmonary hypertension (PH). HNE inhibitors should reestablish the protease-anti-protease balance. By means of medicinal chemistry a novel dihydropyrimidinone lead-structure class was identified. Further chemical optimization yielded orally active compounds with favorable pharmacokinetics such as the chemical probe BAY-678. While maintaining outstanding target selectivity, picomolar potency was achieved by locking the bioactive conformation of these inhibitors with a strategically positioned methyl sulfone substituent. An induced-fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE. BAY 85-8501 ((4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluorometh yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) was shown to be efficacious in a rodent animal model related to ALI. BAY 85-8501 is currently being tested in clinical studies for the treatment of pulmonary diseases. Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases.,von Nussbaum F, Li VM, Allerheiligen S, Anlauf S, Barfacker L, Bechem M, Delbeck M, Fitzgerald MF, Gerisch M, Gielen-Haertwig H, Haning H, Karthaus D, Lang D, Lustig K, Meibom D, Mittendorf J, Rosentreter U, Schafer M, Schafer S, Schamberger J, Telan LA, Tersteegen A ChemMedChem. 2015 Jul;10(7):1163-73. doi: 10.1002/cmdc.201500131. Epub 2015 Jun, 17. PMID:26083237[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Leukocyte elastase | Allerheiligen, S | Anlauf, S | Baerfacker, L | Bechem, M | Delbeck, M | Fitzgerald, M F | Gerisch, M | Gielen-Haertwig, H | Haning, H | Karthaus, D | Lang, D | Li, V M.J | Lustig, K | Meibom, D | Mittendorf, J | Rosentreter, U | Schaefer, M | Schaefer, S | Schamberger, J | Telan, L A | Tersteegen, A | VonNussbaum, F | Hydrolase | Hydrolase- inhibitor complex | Protease | Trypsin family fold
