2. Academic Validation
  3. Analogues of the pan-selectin antagonist rivipansel (GMI-1070)

Analogues of the pan-selectin antagonist rivipansel (GMI-1070)

  • Eur J Med Chem. 2024 Jun 5:272:116455. doi: 10.1016/j.ejmech.2024.116455.
Beatrice Wagner 1,  Martin Smieško 2,  Roman P Jakob 3,  Tobias Mühlethaler 1,  Jonathan Cramer 4,  Tim Maier 3,  Said Rabbani 1,  Oliver Schwardt 1,  Beat Ernst 5
Affiliations

Affiliations

  • 1 University of Basel, Department of Pharmaceutical Sciences, Group Molecular Pharmacy, Klingelbergstrasse 50, 4056, Basel, Switzerland.
  • 2 University of Basel, Department of Pharmaceutical Sciences, Group Computational Pharmacy, Klingelbergstrasse 50, 4056, Basel, Switzerland.
  • 3 University of Basel, Department Biozentrum, Structural Area Focal Biology, Spitalstrasse 41, 4056, Basel, Switzerland.
  • 4 Institute for Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany.
  • 5 University of Basel, Department of Pharmaceutical Sciences, Group Molecular Pharmacy, Klingelbergstrasse 50, 4056, Basel, Switzerland. Electronic address: beat.ernst@unibas.ch.
PMID: 38728868 DOI: 10.1016/j.ejmech.2024.116455
Abstract

The Selectin family consisting of E-, P- and L-selectin plays dominant roles in atherosclerosis, ischemia-reperfusion injury, inflammatory diseases, and metastatic spreading of some cancers. An early goal in selectin-targeted drug discovery campaigns was to identify ligands binding to all three selectins, so-called pan-selectin antagonists. The physiological epitope, tetrasaccharide sialyl Lewisx (sLex, 1) binds to all selectins, albeit with very different affinities. Whereas P- and L-selectin require additional interactions contributed by sulfate groups for high binding affinity, E-Selectin can functionally bind sLex-modified glycolipids and glycoproteins. Rivipansel (3) marked the first pan-selectin antagonist, which simultaneously interacted with both the sLex and the sulfate binding site. The aim of this contribution was to improve the pan-selectin affinity of rivipansel (3) by leveraging a new class of sLex mimetics in combination with an optimized linker length to the sulfate bearing group. As a result, the pan-selectin antagonist 11b exhibits an approximatively 5-fold improved affinity for E-, as well as P-selectin.

Keywords

Glycomimetics; PSGL-1; Pan-selectin antagonist; Rivipansel; Sickle cell disease.

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