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Science

Modulators of protease-activated receptors (PARs)

Protease-activated receptors (PARs) are a unique family of G protein-coupled receptors (GPCRs) that are activated by the cleavage of their N-terminal ends by proteases such as thrombin and trypsin. They play critical roles in platelet activation and clot formation, immune response, inflammation, and potentially cell proliferation and migration. Work from the lab of SAB member Dr. Robert Flaumenhaft and the founder's lab (Dr. Chris Dockendorff) led to the identification of small molecules that can selectively inhibit and activate specific signaling pathways governed by the receptor PAR1. This can result in the inhibition of platelet activation (and resulting thrombus formation), but additionally it leads to the inhibition of inflammatory responses in several cell types, particularly the endothelial cells that comprise the barrier of blood vessels. These molecules, called parmodulins, can also promote protective effects in response to cytokines such as TNF-α, making them promising for the treatment of inflammation-related conditions including sepsis and kidney disease, in addition to thrombosis (see "Projects" section).

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Publications from our collaborating labs:

Reversal of the renal hyperglycemic memory by targeting sustained tubular p21 expression. Al-Dabet, M. M.; Shahzad, K.; Elwakiel, A.; Sulaj, A.; Kopf, S.; Bock, F.; Gadi, I.; Zimmermann, S.; Rana, R.; Krishnan, S.; Gupta, D.; Nazir, S.; Geffers, R.; Mertens, P.; Nawroth, P. P.; Griffin, J.; Dockendorff, C.; Kohli, S.*; Isermann, B.* Nature Communications 2022, 13, 5062.

The Evolving Concept of Neuro-Thromboinflammation for Neurodegenerative Disorders and Neurotrauma: a Rationale for PAR1-Targeting Therapies. Festoff, B. W.*; Dockendorff, C. Biomolecules 2021, 11, 1558.

 

A Thrombin-PAR1/2 Feedback Loop Amplifies Thrombo-Inflammatory Endothelial Responses To The Viral RNA Analogue Poly(I:C). Subramaniam, S.; Ogoti, Y.; Hernandez, I.; Zogg, M.; Botros, F.; Burns, R. T.; DeRousse, J. T.; Dockendorff, C.; Mackman, N.; Antoniak, S.; Fletcher, C.; Weiler, H. Blood Advances 2021, 5, 2760–2774.

Synthesis and initial pharmacology of dual-targeting ligands for putative complexes of integrin αVβ3 and PAR2. Majewski, M. W.; Gandhi, D. M.; Holyst, T.; Wang, Z.; Hernandez, I.; Rosas Jr., R.; Zhu, J.; Weiler, H.; Dockendorff, C.* RSC Med. Chem. 202011, 940–949.

 

The parmodulin NRD-21 is a biased allosteric inhibitor of PAR1 Gq signaling with improved anti-inflammatory activity and stability. Gandhi, D. M.; Rosas, Jr., R.; Greve, E.; Kentala, K.; Diby, N. D.-R.; Snyder, V. A.; Stephans, A.; Yeung, T. H. W.; Subramaniam, S.; DiMilo, E.; Kurtenbach, K. E.; Arnold, L. A.; Weiler, H.; Dockendorff, C.* Bioorg. Med. Chem. 201927, 3788–3796.

 

Design and evaluation of heterobivalent PAR1–PAR2 ligands as antagonists of calcium mobilization. Majewski, M. W.; Gandhi, D. M.; Rosas Jr., R.; Dockendorff, C.* ACS Med. Chem. Lett. 201910, 121–126.

 

Characterization of Protease-Activated Receptor (PAR) ligands: Parmodulins are reversible allosteric inhibitors of PAR1-driven calcium mobilization in endothelial cells. Gandhi, D. M.; Majewski, M. W.; Rosas, Jr., R.; Kentala, K.; Foster, T. J.; Greve, E.; Dockendorff, C.* Bioorg. Med. Chem. 201826, 2514–2529.

 

PAR1 agonists stimulate APC-like endothelial cytoprotection and confer resistance to thromboinflammatory injury. De Ceunynck, K.; Peters, C. G.; Jain, A.; Higgins, S. J.; Aisiku, O.; Fitch-Tewfik, J. L.; Chaudhry, S. A.; Dockendorff, C.; Parikh, S. M.; Ingber, D. E.; Flaumenhaft, R.* Proc. Nat. Acad. Sci. USA 2018115, E982–E991.

 

Cytoprotective activated protein C ameliorates Nlrp3 inflammasome induced ischemia reperfusion 1 injury via mTORC1 inhibition. Nazir, S.; Gadi, I.; Al-Dabet, M. M.; Elwakiel, A.; Kohli, S.; Ghosh, S.; Manoharan, J.; Ranjan, S.; Bock, F.; Braun-Dullaeus, R. C.; Esmon, C. T.; Huber, T. B.; Camerer, E.; Dockendorff, C.; Griffin, J. H.; Isermann, B.*; Shahzad, K.* Blood 2017130, 2664–2677.

 

Parmodulins Inhibit Thrombus Formation Without Inducing Endothelial Injury Caused by Vorapaxar. Aisiku, O.; Peters, C. G.; De Cuenynck, K.; Ghosh, C. C.; Dilks, J. R.; Fustolo-Gunnink, S. F.; Huang, M.; Dockendorff, C.; Parikh, S. M.; Flaumenhaft, R.* Blood 2015125, 1976–1985.

 

Discovery of 1,3-Diaminobenzenes as Selective Inhibitors of Platelet Activation at the PAR1 Receptor. Dockendorff, C.*; Aisiku, O.; VerPlank, L.; Dilks, J. R.; Smith, D. A.; Gunnink, S. F.; Dowal, L.; Negri, J.; Palmer, M.; MacPherson, L.; Schreiber, S. L.; Flaumenhaft, R.* ACS Med. Chem. Lett. 20123, 232–237.