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Full-Text Articles in Chemistry
Characterization Of Protease-Activated Receptor (Par) Ligands: Parmodulins Are Reversible Allosteric Inhibitors Of Par1-Driven Calcium Mobilization In Endothelial Cells, Disha M. Gandhi, Mark W. Majewski, Ricardo Rosas Jr., Kaitlin Kentala, Trevor J. Foster, Eric Greve, Chris Dockendorff
Characterization Of Protease-Activated Receptor (Par) Ligands: Parmodulins Are Reversible Allosteric Inhibitors Of Par1-Driven Calcium Mobilization In Endothelial Cells, Disha M. Gandhi, Mark W. Majewski, Ricardo Rosas Jr., Kaitlin Kentala, Trevor J. Foster, Eric Greve, Chris Dockendorff
Chemistry Faculty Research and Publications
Several classes of ligands for Protease-Activated Receptors (PARs) have shown impressive anti-inflammatory and cytoprotective activities, including PAR2 antagonists and the PAR1-targeting parmodulins. In order to support medicinal chemistry studies with hundreds of compounds and to perform detailed mode-of-action studies, it became important to develop a reliable PAR assay that is operational with endothelial cells, which mediate the cytoprotective effects of interest. We report a detailed protocol for an intracellular calcium mobilization assay with adherent endothelial cells in multiwell plates that was used to study a number of known and new PAR1 and PAR2 ligands, including an alkynylated version of the …
Par1 Agonists Stimulate Apc-Like Endothelial Cytoprotection And Confer Resistance To Thromboinflammatory Injury, Karen De Ceunynck, Christian G. Peters, Abhishek Jain, Sarah J. Higgins, Omozuanvbo Aisiku, Jennifer L. Fitch-Tewfik, Sharjeel A. Chaudhry, Chris Dockendorff, Samir M. Parikh, Donald E. Ingber, Robert Flaumenhaft
Par1 Agonists Stimulate Apc-Like Endothelial Cytoprotection And Confer Resistance To Thromboinflammatory Injury, Karen De Ceunynck, Christian G. Peters, Abhishek Jain, Sarah J. Higgins, Omozuanvbo Aisiku, Jennifer L. Fitch-Tewfik, Sharjeel A. Chaudhry, Chris Dockendorff, Samir M. Parikh, Donald E. Ingber, Robert Flaumenhaft
Chemistry Faculty Research and Publications
Stimulation of protease-activated receptor 1 (PAR1) on endothelium by activated protein C (APC) is protective in several animal models of disease, and APC has been used clinically in severe sepsis and wound healing. Clinical use of APC, however, is limited by its immunogenicity and its anticoagulant activity. We show that a class of small molecules termed “parmodulins” that act at the cytosolic face of PAR1 stimulates APC-like cytoprotective signaling in endothelium. Parmodulins block thrombin generation in response to inflammatory mediators and inhibit platelet accumulation on endothelium cultured under flow. Evaluation of the antithrombotic mechanism showed that parmodulins induce cytoprotective signaling …