Your browser doesn't support javascript.
loading
Glycopeptide analogues of PSGL-1 inhibit P-selectin in vitro and in vivo.
Krishnamurthy, Venkata R; Sardar, Mohammed Y R; Ying, Yu; Song, Xuezheng; Haller, Carolyn; Dai, Erbin; Wang, Xiaocong; Hanjaya-Putra, Donny; Sun, Lijun; Morikis, Vasilios; Simon, Scott I; Woods, Robert J; Cummings, Richard D; Chaikof, Elliot L.
Afiliação
  • Krishnamurthy VR; 1] Department of Surgery, Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Suite 9F, Boston, Massachusetts 02215, USA [2] Wyss Institute of Biologically Inspired Engineering, Harvard University, 110 Francis Street
  • Sardar MY; 1] Department of Surgery, Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Suite 9F, Boston, Massachusetts 02215, USA [2] Wyss Institute of Biologically Inspired Engineering, Harvard University, 110 Francis Street
  • Ying Y; Department of Biochemistry, Emory University, Atlanta, Georgia 30322, USA.
  • Song X; Department of Biochemistry, Emory University, Atlanta, Georgia 30322, USA.
  • Haller C; 1] Department of Surgery, Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Suite 9F, Boston, Massachusetts 02215, USA [2] Wyss Institute of Biologically Inspired Engineering, Harvard University, 110 Francis Street
  • Dai E; 1] Department of Surgery, Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Suite 9F, Boston, Massachusetts 02215, USA [2] Wyss Institute of Biologically Inspired Engineering, Harvard University, 110 Francis Street
  • Wang X; Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602, USA.
  • Hanjaya-Putra D; 1] Department of Surgery, Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Suite 9F, Boston, Massachusetts 02215, USA [2] Wyss Institute of Biologically Inspired Engineering, Harvard University, 110 Francis Street
  • Sun L; Department of Surgery, Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Suite 9F, Boston, Massachusetts 02215, USA.
  • Morikis V; Department of Biomedical Engineering, University of California Davis, Davis, California 95616, USA.
  • Simon SI; Department of Biomedical Engineering, University of California Davis, Davis, California 95616, USA.
  • Woods RJ; 1] Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602, USA [2] School of Chemistry, National University of Ireland, Galway, University Road, Galway, Ireland.
  • Cummings RD; Department of Biochemistry, Emory University, Atlanta, Georgia 30322, USA.
  • Chaikof EL; 1] Department of Surgery, Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Suite 9F, Boston, Massachusetts 02215, USA [2] Wyss Institute of Biologically Inspired Engineering, Harvard University, 110 Francis Street
Nat Commun ; 6: 6387, 2015 Mar 31.
Article em En | MEDLINE | ID: mdl-25824568
Blockade of P-selectin (P-sel)/PSGL-1 interactions holds significant potential for treatment of disorders of innate immunity, thrombosis and cancer. Current inhibitors remain limited due to low binding affinity or by the recognized disadvantages inherent to chronic administration of antibody therapeutics. Here we report an efficient approach for generating glycosulfopeptide mimics of N-terminal PSGL-1 through development of a stereoselective route for multi-gram scale synthesis of the C2 O-glycan building block and replacement of hydrolytically labile tyrosine sulfates with isosteric sulfonate analogues. Library screening afforded a compound of exceptional stability, GSnP-6, that binds to human P-sel with nanomolar affinity (Kd~22 nM). Molecular dynamics simulation defines the origin of this affinity in terms of a number of critical structural contributions. GSnP-6 potently blocks P-sel/PSGL-1 interactions in vitro and in vivo and represents a promising candidate for the treatment of diseases driven by acute and chronic inflammation.
Assuntos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Temas: Geral Base de dados: MEDLINE Assunto principal: Glicoproteínas de Membrana / Glicopeptídeos / Monócitos / Adesão Celular / Músculo Esquelético / Selectina-P / Neutrófilos Limite: Animals / Humans / Male Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2015 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Temas: Geral Base de dados: MEDLINE Assunto principal: Glicoproteínas de Membrana / Glicopeptídeos / Monócitos / Adesão Celular / Músculo Esquelético / Selectina-P / Neutrófilos Limite: Animals / Humans / Male Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2015 Tipo de documento: Article