title: Glycopeptide analogues of PSGL-1 inhibit P-selectin in vitro and in vivo.
abstract: 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.
authors.affiliation: 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, Suite 9F, Boston, Massachusetts 02115, USA.
authors.forename: Venkata R
authors.initials: VR
authors.lastname: Krishnamurthy
authors.affiliation: 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, Suite 9F, Boston, Massachusetts 02115, USA.
authors.forename: Mohammed Y R
authors.initials: MY
authors.lastname: Sardar
authors.affiliation: Department of Biochemistry, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ying
authors.affiliation: Department of Biochemistry, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Xuezheng
authors.initials: X
authors.lastname: Song
authors.affiliation: 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, Suite 9F, Boston, Massachusetts 02115, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Haller
authors.affiliation: 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, Suite 9F, Boston, Massachusetts 02115, USA.
authors.forename: Erbin
authors.initials: E
authors.lastname: Dai
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602, USA.
authors.forename: Xiaocong
authors.initials: X
authors.lastname: Wang
authors.affiliation: 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, Suite 9F, Boston, Massachusetts 02115, USA.
authors.forename: Donny
authors.initials: D
authors.lastname: Hanjaya-Putra
authors.affiliation: 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.
authors.forename: Lijun
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Biomedical Engineering, University of California Davis, Davis, California 95616, USA.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Morikis
authors.affiliation: Department of Biomedical Engineering, University of California Davis, Davis, California 95616, USA.
authors.forename: Scott I
authors.initials: SI
authors.lastname: Simon
authors.affiliation: 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.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Woods
authors.affiliation: Department of Biochemistry, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Cummings
authors.affiliation: 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, Suite 9F, Boston, Massachusetts 02115, USA.
authors.forename: Elliot L
authors.initials: EL
authors.lastname: Chaikof
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects*; D002449:Cell Aggregation / Q000187:drug effects; D002460:Cell Line; D019040:E-Selectin / Q000378:metabolism; D005434:Flow Cytometry; D006020:Glycopeptides / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D019041:L-Selectin / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D056004:Molecular Dynamics Simulation; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D019007:P-Selectin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding
chemical_list: D019040:E-Selectin; D006020:Glycopeptides; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D019041:L-Selectin
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