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revised on 22.09.2019 and posted on 26.09.2019by Mark Majewski, Disha Gandhi, Trudy Holyst, Zhengli Wang, Irene Hernandez, Ricardo Rosas, Jr., Saravanan Subramaniam, Jieqing Zhu, Hartmut Weiler, Chris Dockendorff
Unpublished data from our labs led us to hypothesize that activated Protein C (aPC) may initiate an anti-inflammatory signal in endothelial cells by modulating both the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 αVβ3 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 heterobivalent ligands composed of modified versions of two αVβ3 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 bivalent ligands are effective binders of αVβ3 and potent agonists of PAR2. These bivalent ligands 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.