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

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. Woods, Richard D. Cummings and Elliot L. Chaikof ()
Additional contact information
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
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
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
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
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
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
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

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7387

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