Inhibition of Arginine Methylation Impairs Platelet Function

Abstract

Protein arginine methyltransferases (PRMTs) catalyse 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 inhibitorshave 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 hours 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 anti-cancer drugs.

Investigating the effects of arginine methylation inhibitors on microdissected brain tumour biopsies maintained in a miniaturised perfusion system

“…This is important because PRMT inhibitors are in clinical trials, and cross-talk events could lead to possible off-target side effects. Indeed, the monitoring of any side-effects of PRMT inhibitors is a recognised need, 82 in particular in the light of recent investigations of the effect of PRMT inhibitors on platelets 83 and the termination of several clinical trials using PRMT1 inhibitors, including GSK3368715 ( e.g. NCT03666988, NCT03854227).…”

Re-mining serum proteomics data reveals extensive post-translational modifications upon Zika and dengue infection

“…60,61 Key platelet proteins are known to be arginine methylated, which may promote aggregation in response to thrombin and collagen. 62 In mouse brain tissue, arginine methylation has been detected in transporters and vesicle proteins as well as in ion channels and receptors, all of which are involved in synaptic transmission. 63…”

Virtual Special Issue: Epigenetics 2022

“…However, epigenetic drugs are increasingly studied in other contexts and developed for treating a range of disorders. Examples published in this collection include the effects of arginine methylation inhibitors on blood platelets, a role for histone kinase inhibitors in neuro­degenerative diseases, and the validation of histone deacetylase 8 (HDAC8) inhibitors for the treatment of acute kidney injury . A noteworthy paper focuses on methods for determining cellular target engagement of inhibitors of selected deacetylases …”