Selective Peptidomimetic Inhibitors of NTMT1/2: Rational Design, Synthesis, Characterization, and Crystallographic Studies
| Autor: | Jinrong Min, Guangping Dong, Rong Huang, Haley V. Parker, Christine E. Schaner Tooley, Nicholas Noinaj, Brianna Mackie, Dongxing Chen, Cheng Dong |
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| Rok vydání: | 2020 |
| Předmět: |
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Molecular Methyltransferase Protein Conformation Stereochemistry Peptidomimetic Cell Chemistry Techniques Synthetic Crystallography X-Ray Methylation 01 natural sciences Article Cofactor 03 medical and health sciences Drug Discovery medicine Humans Enzyme Inhibitors Binding site IC50 Mitosis 030304 developmental biology 0303 health sciences biology 010405 organic chemistry Chemistry Rational design Methyltransferases HCT116 Cells 0104 chemical sciences 010404 medicinal & biomolecular chemistry medicine.anatomical_structure Drug Design biology.protein Molecular Medicine Peptidomimetics |
| Zdroj: | J Med Chem |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.0c00689 |
| Popis: | Protein N-terminal methyltransferases (NTMTs) methylate the α-N-terminal amines of proteins starting with the canonical X-P-K/R motif. Genetic studies imply that NTMT1 regulates cell mitosis and DNA damage repair. Herein, we report the rational design and development of the first potent peptidomimetic inhibitors for NTMT1. Biochemical and co-crystallization studies manifest that BM30 (IC50 of 0.89 ± 0.10 µM) is a competitive inhibitor to the peptide substrate and noncompetitive to the cofactor S-adenosylmethionine. BM30 exhibits over 100-fold selectivity to NTMT1/2 among a panel of 41 methyltransferases, indicating the potential to achieve high selectivity when targeting the peptide substrate binding site of NTMT1/2. Its cell-permeable analog DC432 (IC50 of 54 ± 4 nM) decreases the N-terminal methylation level of SET protein in HCT116 cells. This proof-of principle study provides valuable probes for NTMT1/2 and highlights the opportunity to develop more cell-potent inhibitors to elucidate the function of NTMTs in future. |
| Databáze: | OpenAIRE |
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