TY - JOUR
T1 - Glycopeptide analogues of PSGL-1 inhibit P-selectin in vitro and in vivo
AU - Krishnamurthy, Venkata R.
AU - Sardar, Mohammed Y R
AU - Ying, Yu
AU - Song, Xuezheng
AU - Haller, Carolyn
AU - Dai, Erbin
AU - Wang, Xiaocong
AU - Hanjaya-Putra, Donny
AU - Sun, Lijun
AU - Morikis, Vasilios
AU - Simon, Scott I.
AU - Woods, Robert J.
AU - Cummings, Richard D.
AU - Chaikof, Elliot L.
PY - 2015/3/31
Y1 - 2015/3/31
N2 - 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 ∼22nM). 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.
AB - 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 ∼22nM). 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.
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U2 - 10.1038/ncomms7387
DO - 10.1038/ncomms7387
M3 - Article
AN - SCOPUS:84926307673
VL - 6
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 6387
ER -