Chiral Sulfoxide-Induced Single Turn Peptide α-Helicity

Abstract

Inducing α-helicity through side-chain cross-linking is a strategy that has been pursued to improve peptide conformational rigidity and bio-availability. Here we describe the preparation of small peptides tethered to chiral sulfoxide-containing macrocyclic rings. Furthermore, a study of structure-activity relationships (SARs) disclosed properties with respect to ring size, sulfur position, oxidation state, and stereochemistry that show a propensity to induce α-helicity. Supporting data include circular dichroism spectroscopy (CD), NMR spectroscopy, and a single crystal X-ray structure for one such stabilized peptide. Finally, theoretical studies are presented to elucidate the effect of chiral sulfoxides in inducing backbone α-helicity.

Effects of chiral center on an all‐hydrocarbon tethered peptide

“…The peptide epimers' conformational preferences were then tested by CD spectroscopy. As shown in Figure C, peptide 1R with longer retention time on HPLC showed more higher helical contents than peptide 1S , which is in agreement with our previous work, demonstrating that the CIH concept could be translated into an all‐hydrocarbon tethered peptide. Notably, the α‐methyl group in the olefinic amino acid is not necessary for constructing CIH helical peptides .…”

“…Recently, our group developed a chirality induced helicity (CIH) strategy by which a precisely positioned chiral center on the tether could dominate the backbone peptides' helicity, with improved cell permeability and binding affinity towards mammal double minute 2 (MDM2) and estrogen receptor alpha (ERα) . This strategy could also be extended to sulfilimide chiral center and sulfoxide chiral center, which provide a valuable modifiable site on the tether . Meanwhile, Moore et al .…”

“…CIH peptides requires a 7‐atom membered tether with a chiral center at the γ position to the peptide's C terminus. No methyl substitution is required…”

Tuning Sulfur Oxidation States on Thioether‐Bridged Peptide Macrocycles for Modulation of Protein Interactions

“…Zhang et al. calculated a N−C−C−S dihedral angle of approximately −66° when the sulfoxide was pointed away from the helix in the R configuration, whereas in the S configuration the sulfoxide oxygen pointed towards the peptide, causing a steric clash that led to an increase in the dihedral angle to −81° . As we were unable to separate the diasteromeric sulfoxide species, we might have enhanced helicity for only one diastereomer.…”

“…on short single‐turn helical macrocycles. Using shorter hydrocarbon linkers, they also observed a reduction in helicity for singly oxidized thioether‐crosslinked peptides to both a sulfoxide and a sulfone . Furthermore, it was observed that only one sulfoxide epimer enhanced the helicity, whereas the other disrupted helicity.…”