ABSTRACT
Lysine-specific demethylase 1 (LSD1) is a promising therapeutic target, especially in cancer treatment. Despite several LSD1 inhibitors being discovered for the cofactor pocket, none are FDA-approved. We aimed to develop stabilized peptides for irreversible LSD1 binding, focusing on unique cysteine residue Cys360 in LSD1 and SNAIL1. We created LSD1 C360-targeting peptides, like cyclic peptide S9-CMC1, using our Cysteine-Methionine cyclization strategy. S9-CMC1 effectively inhibited LSD1 at the protein level, as confirmed by MS analysis showing covalent bonding to Cys360. In cells, S9-CMC1 inhibited LSD1 activity, increasing H3K4me1 and H3K4me2 levels, leading to G1 cell cycle arrest and apoptosis and inhibiting cell proliferation. Remarkably, S9-CMC1 showed therapeutic potential in A549 xenograft animal models, regulating LSD1 activity and significantly inhibiting tumor growth with minimal organ damage. These findings suggest LSD1 C360 as a promising site for covalent LSD1 inhibitors' development.
Subject(s)
Cysteine , Neoplasms , Animals , Humans , Peptides/pharmacology , Peptides, Cyclic/pharmacology , Peptides, Cyclic/therapeutic use , Cell Proliferation , Histone Demethylases/metabolism , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Cell Line, TumorABSTRACT
Through systematic optimization of halopyridinium compounds, we established a peptide coupling protocol utilizing 4-iodine N-methylpyridinium (4IMP) for solid-phase peptide synthesis (SPPS). The 4IMP coupling reagent is easily prepared, bench stable, and cost-effective. Employing 4IMP in the SPPS process has showcased remarkable chemoselectivity and efficiency, effectively eliminating racemization and epimerization. This achievement has been substantiated through the successful synthesis of a range of peptides via the direct utilization of commercially available amino acid substrates for SPPS.
Subject(s)
Peptides , Pyridinium Compounds , Peptides/chemistry , Amino Acids/chemistry , Solid-Phase Synthesis Techniques/methodsABSTRACT
Continuous efforts have been invested in the selective modification of proteins. Herein, we first report the construction of sulfonium tethered cyclic peptides via an intramolecular cyclization by an aliphatic halide. This cyclization could enhance the stability and cellular uptake of peptides. Furthermore, the sulfonium center could be recognized by cysteine in the vicinity of the protein-peptide interacting interface and form a peptide-protein conjugate.
