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Inhibition of arginine methylation impairs platelet function

Marsden, Alistair James; Riley, David R. J.; Barry, Antonia; Khalil, Jawad S; Guinn, Barbara Ann; Kemp, Neil T.; Rivero, Francisco; Beltran-Alvarez, Pedro

Authors

Alistair James Marsden

David R. J. Riley

Antonia Barry

Jawad S Khalil

Neil T. Kemp

Francisco Rivero



Abstract

Protein arginine methyltransferases (PRMTs) catalyze the transfer of methyl groups to arginine residues in proteins. PRMT inhibitors are novel, promising drugs against cancer that are currently in clinical trials, which include oral administration of the drugs. However, off-target activities of systemically available PRMT inhibitors have not yet been investigated. In this work, we study the relevance of arginine methylation in platelets and investigate the effect of PRMT inhibitors on platelet function and on the expression of relevant platelet receptors. We show that (1) key platelet proteins are modified by arginine methylation; (2) incubation of human platelets with PRMT inhibitors for 4 h results in impaired capacity of platelets to aggregate in response to thrombin and collagen, with IC50 values in the μM range; and (3) treatment with PRMT inhibitors leads to decreased membrane expression and reduced activation of the critical platelet integrin αIIbβ3. Our contribution opens new avenues for research on arginine methylation in platelets, including the repurposing of arginine methylation inhibitors as novel antiplatelet drugs. We also recommend that current and future clinical trials with PRMT inhibitors consider any adverse effects associated with platelet inhibition of these emerging anticancer drugs.

Citation

Khalil, J. S., Riley, D. R., Marsden, A. J., Riley, D. R., Barry, A., Khalil, J. S., …Beltran-Alvarez, P. (in press). Inhibition of arginine methylation impairs platelet function. ACS Pharmacology & Translational Science, https://doi.org/10.1021/acsptsci.1c00135

Journal Article Type Article
Acceptance Date Jul 30, 2021
Online Publication Date Aug 9, 2021
Deposit Date Aug 1, 2021
Publicly Available Date Aug 10, 2022
Journal ACS Pharmacology and Translational Science
Electronic ISSN 2575-9108
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
DOI https://doi.org/10.1021/acsptsci.1c00135
Keywords Antiplatelet; Arginine methylation; Cancer; Inhibitor; Platelet; Protein arginine methyltransferase
Public URL https://hull-repository.worktribe.com/output/3815027