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, Elliot L. Chaikof

Research output: Contribution to journalArticle

27 Scopus citations

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 ∼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.

Original languageEnglish (US)
Article number6387
JournalNature Communications
Volume6
DOIs
StatePublished - Mar 31 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Fingerprint Dive into the research topics of 'Glycopeptide analogues of PSGL-1 inhibit P-selectin in vitro and in vivo'. Together they form a unique fingerprint.

  • Cite this

    Krishnamurthy, V. R., Sardar, M. Y. R., Ying, Y., Song, X., Haller, C., Dai, E., Wang, X., Hanjaya-Putra, D., Sun, L., Morikis, V., Simon, S. I., Woods, R. J., Cummings, R. D., & Chaikof, E. L. (2015). Glycopeptide analogues of PSGL-1 inhibit P-selectin in vitro and in vivo. Nature Communications, 6, [6387]. https://doi.org/10.1038/ncomms7387