Glycopeptide analogues of psgl-1 inhibit p-selectin in vitro and in vivo
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2015-03-31Author
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.
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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. (2015). Glycopeptide analogues of psgl-1 inhibit p-selectin in vitro and in vivo. Nature Communications 6 ,
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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 (K-d similar to 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.