Document Report Card

ID: ALA4699422

Journal: RSC Med Chem

Title: Synthesis and initial pharmacology of dual-targeting ligands for putative complexes of integrin alphaVbeta3 and PAR2

Authors: Majewski, Mark W., Gandhi, Disha M., Holyst, Trudy, Wang, Zhengli, Hernandez, Irene, Rosas, Ricardo, Zhu, Jieqing, Weiler, Hartmut, Dockendorff, Chris

Abstract: Unpublished data from our labs led us to hypothesize that activated protein C (aPC) may initiate an anti-inflammatory signal in endothelial cells by modulating both the integrin alphaVbeta3 and protease-activated receptor 2 (PAR2), which may exist in close proximity on the cellular surface. To test this hypothesis and to probe the possible inflammation-related pathway, we designed and synthesized dual-targeting ligands composed of modified versions of two alphaVbeta3 ligands and two agonists of PAR2. These novel ligands were connected via copper-catalyzed alkyne-azide cycloadditions with polyethylene glycol (PEG) spacers of variable length. Initial in vitro pharmacology with EA.hy926 and HUVEC endothelial cells indicated that these ligands are effective binders of alphaVbeta3 and potent agonists of PAR2. These were also used in preliminary studies investigating their effects on PAR2 signaling in the presence of inflammatory agents, and represent the first examples of ligands targeting both PARs and integrins, though concurrent binding to alphaVbeta3 and PAR2 has not yet been demonstrated.

CiteXplore: 33479689

DOI: 10.1039/d0md00098a