000481559 001__ 481559
000481559 005__ 20250724151718.0
000481559 0247_ $$2doi$$a10.1021/acs.jmedchem.2c00904
000481559 0247_ $$2ISSN$$a0022-2623
000481559 0247_ $$2ISSN$$a0095-9065
000481559 0247_ $$2ISSN$$a1520-4804
000481559 0247_ $$2ISSN$$a1943-2992
000481559 0247_ $$2datacite_doi$$a10.3204/PUBDB-2022-04452
000481559 0247_ $$2altmetric$$aaltmetric:132684419
000481559 0247_ $$2pmid$$apmid:35833347
000481559 0247_ $$2WOS$$aWOS:000830067600001
000481559 0247_ $$2openalex$$aopenalex:W4285388169
000481559 037__ $$aPUBDB-2022-04452
000481559 041__ $$aEnglish
000481559 082__ $$a610
000481559 1001_ $$aVourloumis, Dionisios$$b0
000481559 245__ $$aDiscovery of Selective Nanomolar Inhibitors for Insulin-Regulated Aminopeptidase Based on α-Hydroxy-β-amino Acid Derivatives of Bestatin
000481559 260__ $$aWashington, DC$$bACS$$c2022
000481559 3367_ $$2DRIVER$$aarticle
000481559 3367_ $$2DataCite$$aOutput Types/Journal article
000481559 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1661417694_3324
000481559 3367_ $$2BibTeX$$aARTICLE
000481559 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000481559 3367_ $$00$$2EndNote$$aJournal Article
000481559 520__ $$aThe oxytocinase subfamily of M1 zinc aminopeptidases comprises emerging drug targets, including the ER-resident aminopeptidases 1 and 2 (ERAP1 and ERAP2) and insulin-regulated aminopeptidase (IRAP); however, reports on clinically relevant inhibitors are limited. Here we report a new synthetic approach of high diastereo- and regioselectivity for functionalization of the α-hydroxy-β-amino acid scaffold of bestatin. Stereochemistry and mechanism of inhibition were investigated by a high-resolution X-ray crystal structure of ERAP1 in complex with a micromolar inhibitor. By exploring the P1 side-chain functionalities, we achieve significant potency and selectivity, and we report a cell-active, low-nanomolar inhibitor of IRAP with >120-fold selectivity over homologous enzymes. X-ray crystallographic analysis of IRAP in complex with this inhibitor suggest that interactions with the GAMEN loop is an unappreciated key determinant for potency and selectivity. Overall, our results suggest that α-hydroxy-β-amino acid derivatives may constitute useful chemical tools and drug leads for this group of aminopeptidases.
000481559 536__ $$0G:(DE-HGF)POF4-6G3$$a6G3 - PETRA III (DESY) (POF4-6G3)$$cPOF4-6G3$$fPOF IV$$x0
000481559 588__ $$aDataset connected to CrossRef, Journals: bib-pubdb1.desy.de
000481559 693__ $$0EXP:(DE-H253)P-P13-20150101$$1EXP:(DE-H253)PETRAIII-20150101$$6EXP:(DE-H253)P-P13-20150101$$aPETRA III$$fPETRA Beamline P13$$x0
000481559 7001_ $$aMavridis, Ioannis$$b1
000481559 7001_ $$aAthanasoulis, Alexandros$$b2
000481559 7001_ $$aTemponeras, Ioannis$$b3
000481559 7001_ $$aKoumantou, Despoina$$b4
000481559 7001_ $$aGiastas, Petros$$b5
000481559 7001_ $$00000-0003-0869-9680$$aMpakali, Anastasia$$b6
000481559 7001_ $$aMagrioti, Victoria$$b7
000481559 7001_ $$aLeib, Jacqueline$$b8
000481559 7001_ $$avan Endert, Peter$$b9
000481559 7001_ $$0P:(DE-HGF)0$$aStratikos, Efstratios$$b10$$eCorresponding author
000481559 7001_ $$0P:(DE-HGF)0$$aPapakyriakou, Athanasios$$b11$$eCorresponding author
000481559 773__ $$0PERI:(DE-600)1491411-6$$a10.1021/acs.jmedchem.2c00904$$gVol. 65, no. 14, p. 10098 - 10117$$n14$$p10098 - 10117$$tJournal of medicinal chemistry$$v65$$x0022-2623$$y2022
000481559 8564_ $$uhttps://pubs.acs.org/doi/full/10.1021/acs.jmedchem.2c00904
000481559 8564_ $$uhttps://bib-pubdb1.desy.de/record/481559/files/Discovery%20of%20Selective%20Nanomolar%20Inhibitors%20for%20Insulin%20Regulated%20Aminopeptidase%20Based%20on%20a%20Hydroxy%20b%20amino%20Acid%20Derivatives%20of%20Bestatin.pdf$$yRestricted
000481559 8564_ $$uhttps://bib-pubdb1.desy.de/record/481559/files/document.pdf$$yPublished on 2022-07-14. Available in OpenAccess from 2023-07-14.
000481559 8564_ $$uhttps://bib-pubdb1.desy.de/record/481559/files/Discovery%20of%20Selective%20Nanomolar%20Inhibitors%20for%20Insulin%20Regulated%20Aminopeptidase%20Based%20on%20a%20Hydroxy%20b%20amino%20Acid%20Derivatives%20of%20Bestatin.pdf?subformat=pdfa$$xpdfa$$yRestricted
000481559 8564_ $$uhttps://bib-pubdb1.desy.de/record/481559/files/document.pdf?subformat=pdfa$$xpdfa$$yPublished on 2022-07-14. Available in OpenAccess from 2023-07-14.
000481559 909CO $$ooai:bib-pubdb1.desy.de:481559$$pdnbdelivery$$pdriver$$pVDB$$popen_access$$popenaire
000481559 9131_ $$0G:(DE-HGF)POF4-6G3$$1G:(DE-HGF)POF4-6G0$$2G:(DE-HGF)POF4-600$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bForschungsbereich Materie$$lGroßgeräte: Materie$$vPETRA III (DESY)$$x0
000481559 9141_ $$y2022
000481559 915__ $$0StatID:(DE-HGF)0200$$2StatID$$aDBCoverage$$bSCOPUS$$d2021-01-30
000481559 915__ $$0StatID:(DE-HGF)0160$$2StatID$$aDBCoverage$$bEssential Science Indicators$$d2021-01-30
000481559 915__ $$0StatID:(DE-HGF)1050$$2StatID$$aDBCoverage$$bBIOSIS Previews$$d2021-01-30
000481559 915__ $$0StatID:(DE-HGF)1190$$2StatID$$aDBCoverage$$bBiological Abstracts$$d2021-01-30
000481559 915__ $$0StatID:(DE-HGF)0600$$2StatID$$aDBCoverage$$bEbsco Academic Search$$d2021-01-30
000481559 915__ $$0StatID:(DE-HGF)0530$$2StatID$$aEmbargoed OpenAccess
000481559 915__ $$0StatID:(DE-HGF)1200$$2StatID$$aDBCoverage$$bChemical Reactions$$d2021-01-30
000481559 915__ $$0StatID:(DE-HGF)9905$$2StatID$$aIF >= 5$$bJ MED CHEM : 2019$$d2021-01-30
000481559 915__ $$0StatID:(DE-HGF)1030$$2StatID$$aDBCoverage$$bCurrent Contents - Life Sciences$$d2021-01-30
000481559 915__ $$0StatID:(DE-HGF)1210$$2StatID$$aDBCoverage$$bIndex Chemicus$$d2021-01-30
000481559 915__ $$0StatID:(DE-HGF)0113$$2StatID$$aWoS$$bScience Citation Index Expanded$$d2021-01-30
000481559 915__ $$0StatID:(DE-HGF)0150$$2StatID$$aDBCoverage$$bWeb of Science Core Collection$$d2021-01-30
000481559 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bASC$$d2021-01-30
000481559 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bJ MED CHEM : 2019$$d2021-01-30
000481559 915__ $$0StatID:(DE-HGF)0300$$2StatID$$aDBCoverage$$bMedline$$d2021-01-30
000481559 915__ $$0StatID:(DE-HGF)0420$$2StatID$$aNationallizenz$$d2021-01-30$$wger
000481559 915__ $$0StatID:(DE-HGF)0199$$2StatID$$aDBCoverage$$bClarivate Analytics Master Journal List$$d2021-01-30
000481559 9201_ $$0I:(DE-H253)EMBL-User-20120814$$kEMBL-User$$lEMBL-User$$x0
000481559 980__ $$ajournal
000481559 980__ $$aVDB
000481559 980__ $$aUNRESTRICTED
000481559 980__ $$aI:(DE-H253)EMBL-User-20120814
000481559 9801_ $$aFullTexts