5abw

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Revision as of 09:43, 22 March 2017

Neutrophil elastase inhibitors for the treatment of (cardio)pulmonary diseases

Structural highlights

5abw is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Activity:	Leukocyte elastase, with EC number 3.4.21.37
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 PubMed

Alpha-1 antitrypsin deficiency is linked with an increased risk of suffering from lung emphysema. This discovery from the 1960s led to the development of the protease-antiprotease (im)balance hypothesis: Overshooting protease concentrations, especially high levels of elastase were deemed to have an destructive effect on lung tissue. Consequently, it was postulated that efficient elastase inhibitors could alleviate the situation in patients. However, despite intensive drug discovery efforts, even five decades later, no neutrophil elastase inhibitors are available for a disease-modifying treatment of (cardio)pulmonary diseases such as chronic obstructive pulmonary disease. Here, we critically review the attempts to develop effective human neutrophil elastase inhibitors while strongly focussing on recent developments. On purpose and with perspective distortion we focus on recent developments. One aim of this review is to classify the known HNE inhibitors into several generations, according to their binding modes. In general, there seem to be three major challenges in the development of suitable elastase inhibitors: (1) assuring sufficient potency, (2) securing selectivity, and (3) achieving metabolic stability especially under pathophysiological conditions. Impressive achievements have been made since 2001 with the identification of potent nonreactive, reversible small molecule inhibitors. The most modern inhibitors bind HNE via an induced fit with a frozen bioactive conformation that leads to a significant boost in potency, selectivity, and stability ('pre-adaptive pharmacophores'). These 5th generation inhibitors might succeed in re-establishing the protease-antiprotease balance in patients for the first time.

Neutrophil elastase inhibitors for the treatment of (cardio)pulmonary diseases: Into clinical testing with pre-adaptive pharmacophores.,von Nussbaum F, Li VM Bioorg Med Chem Lett. 2015 Oct 15;25(20):4370-81. doi:, 10.1016/j.bmcl.2015.08.049. Epub 2015 Aug 20. PMID:26358162^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Duan Z, Li FQ, Wechsler J, Meade-White K, Williams K, Benson KF, Horwitz M. A novel notch protein, N2N, targeted by neutrophil elastase and implicated in hereditary neutropenia. Mol Cell Biol. 2004 Jan;24(1):58-70. PMID:14673143
↑ Horwitz M, Benson KF, Person RE, Aprikyan AG, Dale DC. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genet. 1999 Dec;23(4):433-6. PMID:10581030 doi:10.1038/70544
↑ Germeshausen M, Zeidler C, Stuhrmann M, Lanciotti M, Ballmaier M, Welte K. Digenic mutations in severe congenital neutropenia. Haematologica. 2010 Jul;95(7):1207-10. doi: 10.3324/haematol.2009.017665. Epub, 2010 Mar 10. PMID:20220065 doi:10.3324/haematol.2009.017665
↑ Tralau T, Meyer-Hoffert U, Schroder JM, Wiedow O. Human leukocyte elastase and cathepsin G are specific inhibitors of C5a-dependent neutrophil enzyme release and chemotaxis. Exp Dermatol. 2004 May;13(5):316-25. PMID:15140022 doi:10.1111/j.0906-6705.2004.00145.x
↑ von Nussbaum F, Li VM. Neutrophil elastase inhibitors for the treatment of (cardio)pulmonary diseases: Into clinical testing with pre-adaptive pharmacophores. Bioorg Med Chem Lett. 2015 Oct 15;25(20):4370-81. doi:, 10.1016/j.bmcl.2015.08.049. Epub 2015 Aug 20. PMID:26358162 doi:http://dx.doi.org/10.1016/j.bmcl.2015.08.049

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5abw"

@@ Line 1: / Line 1: @@
 ==Neutrophil elastase inhibitors for the treatment of (cardio)pulmonary diseases==
 <StructureSection load='5abw' size='340' side='right' caption='[[5abw]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[5abw]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ABW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ABW FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=WQQ:1-(3-CHLOROPHENYL)-5-(3,5-DIMETHYLISOXAZOL-4-YL)-6-METHYL-N-[4-(METHYLSULFONYL)BENZYL]-2-OXO-1,2-DIHYDROPYRIDINE-3-CARBOXAMIDE'>WQQ</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=WQQ:1-(3-CHLOROPHENYL)-5-(3,5-DIMETHYLISOXAZOL-4-YL)-6-METHYL-N-[4-(METHYLSULFONYL)BENZYL]-2-OXO-1,2-DIHYDROPYRIDINE-3-CARBOXAMIDE'>WQQ</scene></td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Leukocyte_elastase Leukocyte elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.37 3.4.21.37] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5abw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5abw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=5abw RCSB], [http://www.ebi.ac.uk/pdbsum/5abw PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5abw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5abw OCA], [http://pdbe.org/5abw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5abw RCSB], [http://www.ebi.ac.uk/pdbsum/5abw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5abw ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 11: / Line 12: @@
 == Function ==
 [[http://www.uniprot.org/uniprot/ELNE_HUMAN ELNE_HUMAN]] Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis.<ref>PMID:15140022</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Alpha-1 antitrypsin deficiency is linked with an increased risk of suffering from lung emphysema. This discovery from the 1960s led to the development of the protease-antiprotease (im)balance hypothesis: Overshooting protease concentrations, especially high levels of elastase were deemed to have an destructive effect on lung tissue. Consequently, it was postulated that efficient elastase inhibitors could alleviate the situation in patients. However, despite intensive drug discovery efforts, even five decades later, no neutrophil elastase inhibitors are available for a disease-modifying treatment of (cardio)pulmonary diseases such as chronic obstructive pulmonary disease. Here, we critically review the attempts to develop effective human neutrophil elastase inhibitors while strongly focussing on recent developments. On purpose and with perspective distortion we focus on recent developments. One aim of this review is to classify the known HNE inhibitors into several generations, according to their binding modes. In general, there seem to be three major challenges in the development of suitable elastase inhibitors: (1) assuring sufficient potency, (2) securing selectivity, and (3) achieving metabolic stability especially under pathophysiological conditions. Impressive achievements have been made since 2001 with the identification of potent nonreactive, reversible small molecule inhibitors. The most modern inhibitors bind HNE via an induced fit with a frozen bioactive conformation that leads to a significant boost in potency, selectivity, and stability ('pre-adaptive pharmacophores'). These 5th generation inhibitors might succeed in re-establishing the protease-antiprotease balance in patients for the first time.
+Neutrophil elastase inhibitors for the treatment of (cardio)pulmonary diseases: Into clinical testing with pre-adaptive pharmacophores.,von Nussbaum F, Li VM Bioorg Med Chem Lett. 2015 Oct 15;25(20):4370-81. doi:, 10.1016/j.bmcl.2015.08.049. Epub 2015 Aug 20. PMID:26358162<ref>PMID:26358162</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 5abw" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

5abw

From Proteopedia

Revision as of 09:43, 22 March 2017

Neutrophil elastase inhibitors for the treatment of (cardio)pulmonary diseases

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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