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dc.contributor.authorKrishnamurthy, Venkata R.
dc.contributor.authorSardar, Mohammed Y. R.
dc.contributor.authorYing, Yu
dc.contributor.authorSong, Xuezheng
dc.contributor.authorHaller, Carolyn
dc.contributor.authorDai, Erbin
dc.contributor.authorWang, Xiaocong
dc.contributor.authorHanjaya-Putra, Donny
dc.contributor.authorSun, Lijun
dc.contributor.authorMorikis, Vasilios
dc.contributor.authorSimon, Scott I.
dc.contributor.authorWoods, Robert J.
dc.contributor.authorCummings, Richard D.
dc.contributor.authorChaikof, Elliot L.
dc.date.accessioned2018-09-20T16:13:34Z
dc.date.available2018-09-20T16:13:34Z
dc.date.issued2015-03-31
dc.identifier.citationKrishnamurthy, 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 ,
dc.identifier.issn2041-1723
dc.identifier.urihttp://hdl.handle.net/10379/12318
dc.description.abstractBlockade 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.
dc.publisherSpringer Nature
dc.relation.ispartofNature Communications
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 Ireland
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/3.0/ie/
dc.subjectsialyl-lewis-x
dc.subjectbinding free-energies
dc.subjectglycoprotein ligand-1
dc.subjecttyrosine-sulfate
dc.subjectendothelial selectins
dc.subjectintegrin activation
dc.subjectleukocyte adhesion
dc.subjecthuman neutrophils
dc.subjectdeficient mice
dc.subjecthiv-1 entry
dc.titleGlycopeptide analogues of psgl-1 inhibit p-selectin in vitro and in vivo
dc.typeArticle
dc.identifier.doi10.1038/ncomms7387
dc.local.publishedsourcehttp://www.nature.com/articles/ncomms7387.pdf
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Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivs 3.0 Ireland