View source for 9si4


==Structure of human neutrophil elastase in complex with a 5,8-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-3(2H)-one inhibitor==
<StructureSection load='9si4' size='340' side='right'caption='[[9si4]], [[Resolution|resolution]] 1.14&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9si4]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9SI4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9SI4 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.14&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JN2:2-[5-cyano-2-[(5~{R})-6-methoxycarbonyl-7-methyl-3-oxidanylidene-8-[3-(trifluoromethyl)phenyl]-2,5-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]phenyl]ethyl-trimethyl-azanium'>A1JN2</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9si4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9si4 OCA], [https://pdbe.org/9si4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9si4 RCSB], [https://www.ebi.ac.uk/pdbsum/9si4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9si4 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/ELNE_HUMAN ELNE_HUMAN] Defects in ELANE are a cause of cyclic haematopoiesis (CH) [MIM:[https://omim.org/entry/162800 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.<ref>PMID:14673143</ref> <ref>PMID:10581030</ref>   Defects in ELANE are the cause of neutropenia severe congenital autosomal dominant type 1 (SCN1) [MIM:[https://omim.org/entry/202700 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.<ref>PMID:20220065</ref> 
== Function ==
[https://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 ==
The inhibitors of neutrophil elastase (NE) have long attracted interest for the treatment of respiratory diseases. We report the breakthrough of a new potent, selective NE inhibitor with a 24 h duration of action: CHF-6333, is currently undergoing clinical studies for the inhaled treatment of bronchiectasis (BE). The story of the discovery project to identify novel small molecules that inhibit extracellular elastase in the lung with prolonged activity is described. Medicinal chemistry investigation, supported by docking studies, led to N-quaternary compounds with an in vitro profile suitable for inhalatory administration. Compound 15 emerged from in vivo pharmacokinetic and pharmacodynamic studies, also showing safety and no off-target effects in vitro. Salt screening of different counterions, in conjunction with in vivo local irritancy testing, aided in the selection of compound 15-xinafoate (CHF-6333). Efficacy in a lung injury model and no findings in non-GLP toxicity studies promoted CHF-6333 as a clinical candidate.

Design, Synthesis, and Biological Evaluation of the Novel Neutrophil Elastase Inhibitor CHF-6333 for the Inhaled Treatment of Bronchiectasis.,Armani E, Rizzi A, Miglietta D, Bassanetti I, Amadei F, Brogin G, Capaldi C, Rancati F, Carnini C, Xanxo Fernandez S, Civelli M, Puccini P, Bellini M, Jennings A, Heald RA, Alcaraz L, Sutton JM, Finch H, Fitzgerald M, Fox C, Villetti G J Med Chem. 2025 Nov 27. doi: 10.1021/acs.jmedchem.5c02638. PMID:41307403<ref>PMID:41307403</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9si4" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Armani E]]
[[Category: Rizzi A]]