Synthesis and initial pharmacology of dual-targeting ligands for putative complexes of integrin αVβ3 and PAR2

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

doi:10.1039/D0MD00098A

Synthesis and initial pharmacology of dual-targeting ligands for putative complexes of integrin αVβ3 and PAR2†

Mark W. Majewski,^a Disha M. Gandhi,^a Trudy Holyst,^b Zhengli Wang,^b Irene Hernandez,^b Ricardo Rosas, Jr.,^a Jieqing Zhu,^bc Hartmut Weiler^bd and Chris Dockendorff

*^a

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* Corresponding authors

^a Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI, USA
E-mail: christopher.dockendorff@mu.edu
Tel: +1 414 288 1617

^b Blood Research Institute, Versiti, Milwaukee, WI, USA

^c Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA

^d Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA

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Unpublished data from our labs led us to hypothesize that activated protein C (aPC) may initiate an anti-inflammatory signal in endothelial cells by modulating both the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 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 dual-targeting 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 ligands are effective binders of αVβ3 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 αVβ3 and PAR2 has not yet been demonstrated.

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DOI: https://doi.org/10.1039/D0MD00098A
Article type: Research Article
Submitted: 29 Mar 2020
Accepted: 24 Jun 2020
First published: 09 Jul 2020

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RSC Med. Chem., 2020,11, 940-949

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Synthesis and initial pharmacology of dual-targeting ligands for putative complexes of integrin αVβ3 and PAR2

M. W. Majewski, D. M. Gandhi, T. Holyst, Z. Wang, I. Hernandez, R. Rosas, J. Zhu, H. Weiler and C. Dockendorff, RSC Med. Chem., 2020, 11, 940 DOI: 10.1039/D0MD00098A

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RSC Medicinal Chemistry

Synthesis and initial pharmacology of dual-targeting ligands for putative complexes of integrin αVβ3 and PAR2†

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Synthesis and initial pharmacology of dual-targeting ligands for putative complexes of integrin αVβ3 and PAR2

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