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Glycopeptide analogues of PSGL-1 inhibit P-selectin in vitro and in vivo

Author

Listed:
  • Venkata R. Krishnamurthy

    (Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Suite 9F, Boston, Massachusetts 02215, USA
    Wyss Institute of Biologically Inspired Engineering, Harvard University, 110 Francis Street, Suite 9F, Boston, Massachusetts 02115, USA)

  • Mohammed Y. R. Sardar

    (Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Suite 9F, Boston, Massachusetts 02215, USA
    Wyss Institute of Biologically Inspired Engineering, Harvard University, 110 Francis Street, Suite 9F, Boston, Massachusetts 02115, USA)

  • Yu Ying

    (Emory University)

  • Xuezheng Song

    (Emory University)

  • Carolyn Haller

    (Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Suite 9F, Boston, Massachusetts 02215, USA
    Wyss Institute of Biologically Inspired Engineering, Harvard University, 110 Francis Street, Suite 9F, Boston, Massachusetts 02115, USA)

  • Erbin Dai

    (Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Suite 9F, Boston, Massachusetts 02215, USA
    Wyss Institute of Biologically Inspired Engineering, Harvard University, 110 Francis Street, Suite 9F, Boston, Massachusetts 02115, USA)

  • Xiaocong Wang

    (Complex Carbohydrate Research Center, University of Georgia)

  • Donny Hanjaya-Putra

    (Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Suite 9F, Boston, Massachusetts 02215, USA
    Wyss Institute of Biologically Inspired Engineering, Harvard University, 110 Francis Street, Suite 9F, Boston, Massachusetts 02115, USA)

  • Lijun Sun

    (Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Suite 9F, Boston, Massachusetts 02215, USA)

  • Vasilios Morikis

    (University of California Davis)

  • Scott I. Simon

    (University of California Davis)

  • Robert J. Woods

    (Complex Carbohydrate Research Center, University of Georgia
    School of Chemistry, National University of Ireland, Galway, University Road, Galway, Ireland)

  • Richard D. Cummings

    (Emory University)

  • Elliot L. Chaikof

    (Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Suite 9F, Boston, Massachusetts 02215, USA
    Wyss Institute of Biologically Inspired Engineering, Harvard University, 110 Francis Street, Suite 9F, Boston, Massachusetts 02115, USA)

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.

Suggested Citation

  • Venkata R. Krishnamurthy & Mohammed Y. R. Sardar & Yu Ying & Xuezheng Song & Carolyn Haller & Erbin Dai & Xiaocong Wang & Donny Hanjaya-Putra & Lijun Sun & Vasilios Morikis & Scott I. Simon & Robert J, 2015. "Glycopeptide analogues of PSGL-1 inhibit P-selectin in vitro and in vivo," Nature Communications, Nature, vol. 6(1), pages 1-12, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7387
    DOI: 10.1038/ncomms7387
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