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

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

Marsden, A. J., Riley, D. R., Barry, A., Khalil, J. S., Guinn, B. A., Kemp, N. T., …Beltran-Alvarez, P. (2021). Inhibition of Arginine Methylation Impairs Platelet Function. ACS Pharmacology & Translational Science, 4(5), 1567-1577. https://doi.org/10.1021/acsptsci.1c00135

• Journal Article Type: Article
• Acceptance Date: Jul 30, 2021
• Online Publication Date: Aug 9, 2021
• Publication Date: Oct 8, 2021
• Deposit Date: Oct 22, 2021
• Publicly Available Date: Oct 22, 2021
• Journal: ACS Pharmacology & Translational Science
• Electronic ISSN: 2575-9108
• Publisher: American Chemical Society (ACS)
• Peer Reviewed: Peer Reviewed
• Volume: 4
• Issue: 5
• Pages: 1567-1577
• DOI: https://doi.org/10.1021/acsptsci.1c00135
• Keywords: Pharmacology (medical); Pharmacology
• Public URL: https://nottingham-repository.worktribe.com/output/6206878
• Publisher URL: https://pubs.acs.org/doi/10.1021/acsptsci.1c00135
• Additional Information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Pharmacology & Translational Science, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acsptsci.1c00135