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Synthesis and Initial Pharmacology of Heterobivalent Ligands Targeting Putative Complexes of Integrin αVβ3 and PAR2

preprint
revised on 22.09.2019 and posted on 26.09.2019 by 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Unpublished data from our labs led us to hypothesize that activated Protein C (aPC) may initiate an anti-inflammatory signal in endothelial cells by modulating both the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.

Funding

Novel Approaches to the Modulation of Protease-Activated Receptor (PAR) Signaling

National Heart Lung and Blood Institute

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Clinical and Translational Science Institute of Southeast Wis-consin: 8UL1TR000055

Regulation of Innate Immunity by Coagulation Receptors

National Heart Lung and Blood Institute

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Structural Transition of Cellular Integrins and Applications Thereof

National Heart Lung and Blood Institute

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History

Email Address of Submitting Author

christopher.dockendorff@mu.edu

Institution

Marquette University

Country

United States

ORCID For Submitting Author

0000-0002-4092-5636

Declaration of Conflict of Interest

No conflict of interest

Version Notes

Version 2 (uploaded 2019 09 21) contains corrections to the experimental details of Figure 5. A complete Supporting Info file is also attached.

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