Peptidic transition state analogues as PRMT inhibitors
Protein arginine N-methyltransferases (PRMTs) methylate arginine residues in target proteins using the ubiquitous methyl donor S-adenosyl-l-methionine (AdoMet) as a cofactor. PRMTs play important roles in both healthy and disease states and as such inhibition of PRMTs has gained increasing interest....
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Veröffentlicht in: | Methods 2019-08, Vol.175, p.24-29 |
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Zusammenfassung: | Protein arginine N-methyltransferases (PRMTs) methylate arginine residues in target proteins using the ubiquitous methyl donor S-adenosyl-l-methionine (AdoMet) as a cofactor. PRMTs play important roles in both healthy and disease states and as such inhibition of PRMTs has gained increasing interest. A primary challenge in the development of PRMT inhibitors is achieving specificity for the PRMT of interest as the active sites are highly conserved for all nine members of the PRMT family. Notably, PRMTs show very little redundancy in vivo due to their specific sets of protein substrates. However, relatively little is known about the interactions of PRMTs with their protein substrates that drive this substrate specificity. We here describe the extended application of a methodology recently developed in our group for the production of peptide-based transition state mimicking PRMT inhibitors. Using this approach, an adenosine moiety, mimicking that of the AdoMet cofactor, is covalently linked to the guanidine side chain of a target arginine residue contained in a peptidic fragment derived from a PRMT substrate protein. Using this approach, histone H4 tail peptide-based transition state mimics were synthesized wherein the adenosine group was linked to the Arg3 residue. H4R3 is a substrate for multiple PRMTs, including PRMT1 and PRMT6. The inhibition results obtained with these new H4-based transition state mimics show low micromolar IC50 values against PRMT1 and PRMT6, indicating that the methodology is applicable to the broader family of PRMTs. |
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DOI: | 10.1016/j.ymeth.2019.08.003 |