β-Actin Peptide-Based Inhibitors of Histidine Methyltransferase SETD3

ChemMedChem. 2021 May 25. doi: 10.1002/cmdc.202100296. Online ahead of print.ABSTRACTSETD3 was recently identified as the histidine methyltransferase responsible for N 3 -methylation of His73 of β-actin in humans. Overexpression of SETD3 is associated with several diseases, including breast cancer. Here, we report a development of actin-based peptidomimetics as inhibitors of recombinantly expressed human SETD3. Substitution of His73 by simple natural and unnatural amino acids led to selected β-actin peptides with high potency against SETD3 in MALDI-TOF MS assays. The selenomethionine-containing β-actin peptide was found to be the most potent SETD3 inhibitor (IC 50 = 161 nM). Supporting our inhibition assays, a combination of computational docking and molecular dynamics simulations revealed that the His73 binding pocket for β-actin in SETD3 is rigid and accommodates the inhibitor peptides with similar binding modes. Collectively, our work demonstrates that actin-based peptidomimetics can act as potent SETD3 inhibitors and provide a basis for further development of highly potent and selective inhibitors of SETD3.PMID:34032009 | DOI:10.1002/cmdc.202100296

Source: ChemMedChem - May 25, 2021 Category: Chemistry Authors: Jordi C J Hintzen Laust Moesgaard Sebastian Kwiatkowski Jakub Drozak Jacob Kongsted Jasmin Mecinovic Source Type: research