# The Identification of a Sub-Micromolar Peptide-Based Protein Arginine Methyltransferase 1 (PRMT1) Inhibitor from a Plate-Based Screening Assay

## TL;DR

Researchers identified a potent inhibitor for PRMT1, an enzyme linked to cancer, by screening a peptide library and analyzing substrate preferences.

## Contribution

A sub-micromolar peptide-based PRMT1 inhibitor was developed, surpassing previous inhibitors in potency.

## Key findings

- Seven peptide sequences were identified as exceptional PRMT1 substrates through screening.
- A peptide-based PRMT1 inhibitor with sub-micromolar potency was developed using a chloroacetamidine warhead.

## Abstract

Post-translational modifications (PTMs) expand the structural diversity of proteins beyond the standard amino acids, influencing protein-protein interactions. Protein methylation, a prevalent PTM, involves the transfer of methyl groups from S-adenosylmethionine (SAM) to lysine and arginine residues. Arginine methylation is catalyzed by the Protein Arginine Methyltransferase (PRMT) family to yield mono- and dimethylarginine forms. PRMT1, the isozyme responsible for the majority of asymmetric dimethylation (ADMA) is implicated in various diseases, including cancer. Here, we report the synthesis and screening of a second-generation peptide library to identify novel PRMT1 substrates. The library, based on histone peptides, incorporated varying sequences of amino acids, facilitating substrate specificity studies. Screening identified 7 peptide sequences as exceptional PRMT1 substrates, which were confirmed by kinetic analysis. Consensus sequences revealed key recognition elements for PRMT1 catalysis, suggesting roles for small non-polar side chains and specific residues near the substrate arginine. Furthermore, we developed a peptide-based PRMT1 inhibitor by substituting the substrate arginine with a chloroacetamidine warhead. The inhibitor exhibited sub-micromolar inhibitory potency against PRMT1, surpassing previous peptide-based inhibitors. Our findings contribute to understanding PRMT1 substrate specificity and provide a scaffold for developing potent inhibitors targeting PRMT1 in diseases, including cancer.