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@ARTICLE{Vourloumis:481559,
      author       = {Vourloumis, Dionisios and Mavridis, Ioannis and
                      Athanasoulis, Alexandros and Temponeras, Ioannis and
                      Koumantou, Despoina and Giastas, Petros and Mpakali,
                      Anastasia and Magrioti, Victoria and Leib, Jacqueline and
                      van Endert, Peter and Stratikos, Efstratios and
                      Papakyriakou, Athanasios},
      title        = {{D}iscovery of {S}elective {N}anomolar {I}nhibitors for
                      {I}nsulin-{R}egulated {A}minopeptidase {B}ased on
                      α-{H}ydroxy-β-amino {A}cid {D}erivatives of {B}estatin},
      journal      = {Journal of medicinal chemistry},
      volume       = {65},
      number       = {14},
      issn         = {0022-2623},
      address      = {Washington, DC},
      publisher    = {ACS},
      reportid     = {PUBDB-2022-04452},
      pages        = {10098 - 10117},
      year         = {2022},
      abstract     = {The 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.},
      cin          = {EMBL-User},
      ddc          = {610},
      cid          = {I:(DE-H253)EMBL-User-20120814},
      pnm          = {6G3 - PETRA III (DESY) (POF4-6G3)},
      pid          = {G:(DE-HGF)POF4-6G3},
      experiment   = {EXP:(DE-H253)P-P13-20150101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35833347},
      UT           = {WOS:000830067600001},
      doi          = {10.1021/acs.jmedchem.2c00904},
      url          = {https://bib-pubdb1.desy.de/record/481559},
}