α‐Aminoxy Oligopeptides: Synthesis, Secondary Structure, and Cytotoxicity of a New Class of Anticancer Foldamers

Abstract

α-Aminoxy peptides are peptidomimetic foldamers with high proteolytic and conformational stability. To gain an improved synthetic access to α-aminoxy oligopeptides we used a straightforward combination of solution- and solid-phase-supported methods and obtained oligomers that showed a remarkable anticancer activity against a panel of cancer cell lines. We solved the first X-ray crystal structure of an α-aminoxy peptide with multiple turns around the helical axis. The crystal structure revealed a right-handed 2 -helical conformation with precisely two residues per turn and a helical pitch of 5.8 Å. By 2D ROESY experiments, molecular dynamics simulations, and CD spectroscopy we were able to identify the 2 -helix as the predominant conformation in organic solvents. In aqueous solution, the α-aminoxy peptides exist in the 2 -helical conformation at acidic pH, but exhibit remarkable changes in the secondary structure with increasing pH. The most cytotoxic α-aminoxy peptides have an increased propensity to take up a 2 -helical conformation in the presence of a model membrane. This indicates a correlation between the 2 -helical conformation and the membranolytic activity observed in mode of action studies, thereby providing novel insights in the folding properties and the biological activity of α-aminoxy peptides.

Partially inserted nascent chain unzips the lateral gate of the Sec translocon

“…For subsequent MD simulations, we used the simulation protocol as described by us previously . In order to set up five independent MD production simulations, the target temperature during thermalization varied from 299.8 to 300.2 K in 0.1 K intervals, so that we obtained five different configurations for subsequent MD production runs.…”

“…The Amber ff14SB force field [68] was used to parametrize the protein, adaptations by Joung and Cheatham [69] were applied to treat K + and Cl À , and the lipid 17 force field distributed with Amber 17 to treat the lipid bilayer. For subsequent MD simulations, we used the simulation protocol as described by us previously [70,71]. In order to set up five independent MD production simulations, the target temperature during thermalization varied from 299.8 to 300.2 K in 0.1 K intervals, so that we obtained five different configurations for subsequent MD production runs.…”

EDTA aggregates induce SYPRO orange-based fluorescence in thermal shift assay

“…cuda module [ 28 ] in Amber 12 [ 22 ]. We applied the MD protocol previously described here [ 29 , 30 ]. In short, we performed three individual rounds of energy minimization with high, low, and no positional restraints applied to all solute atoms.…”

Improvement in the catalytic performance of a phenylpyruvate reductase from Lactobacillus plantarum by site-directed and saturation mutagenesis based on the computer-aided design

“…The optically pure PLAs, L-PLA and d-PLA, were also highly value-added and versatile building blocks for the synthesis of several bioactive compounds in the pharmaceutical and fine chemical industries. For instance, D-PLA was an important intermediate for the synthesis of a hypoglycemic agent Englitazone (Xu et al 2016), and a series of α-aminoxy peptides having potential anticancer activities (Diedrich et al 2016). Additionally, D-PLA was also applied to the synthesis of poly d-phenyllactic acid having superior hydrophobicity and toughness, a potential alternative for poly d-lactic acid (Fujita et al 2013).…”