Selective cleavage of an azaGly peptide bond by copper(II). Long‐range effect of histidine residue

Abstract

Several reports have highlighted the interest of replacing Gly, a frequent amino acid within bioactive peptides, by azaGly (Agly) to improve their stability, activity or for the design of prodrugs. Because metal catalysis is increasingly used for tailoring peptide molecules, we have studied the stability of Agly peptides in the presence of metal ions. In this study, we show that Cu(II), unlike other metal ions such as Fe(II), Fe(III), Pd(II), or Pt(II), induces the cleavage of Agly peptides at room temperature and pH 7.3. The cleavage occurred in the absence of an anchoring His residue within the peptide but it was accelerated when this amino acid was present in the sequence. The influence of His residue on the cleavage rate was minimal when His and Agly were adjacent, whereas large effects were observed for distant His residues. The reaction between Cu(II) and Agly peptides induced the formation of Cu(I) species, which could be detected using bicinchoninic acid as a probe. The nature of products formed in this reaction allowed suggesting a mechanism for the Cu(II)-induced cleavage of Agly peptides.

Clickable, Hydrophilic Ligand forfac-[MI(CO)3]+(M = Re/99mTc) Applied in anS-Functionalized α-MSH Peptide

“…RP-HPLC analysis of 9a and 10a produced via the click, then chelate route, however, showed multiple species at times beyond 2 h in the above challenge conditions and when incubated in PBS at room temperature following purification (data not shown). This suggests that residual copper which was apparent in peptides 7 and 8 prior to complexation with the fac -[ 99m Tc I (CO) 3 ] + core led to less stable coordination modes or may have negatively impacted the integrity of the radiolabeled peptides (e.g., through metal-mediated peptide hydrolysis , ). Employing the precomplexed ligands in the chelate, then click strategy did not suffer these drawbacks, thus highlighting the benefit of this synthetic pathway for generating the desired fac -[ 99m Tc I (CO) 3 ] + -complexed peptides, 9a′ and 10a′ .…”

Phenylthiocarbamate orN-Carbothiophenyl Group Chemistry in Peptide Synthesis and Bioconjugation

“…Agly can be incorporated into peptides using well-developed SPPS methods. ,,− Alternatively, the preparation of large Agly peptides or conjugates is best carried out in solution using chemoselective ligation methods. Agly ligation between a hydrazide 47 and an N-terminal phenylthiocarbonyl peptide 48 in the presence of silver ions offers a potential solution to this problem (Scheme ) …”

Late-Stage N-Alkylation of Azapeptides

“…We envisioned that the difference in p K a values between acyl hydrazides and amides would enable selective functionalization of aza-amino acids embedded in peptides . On-resin chemoselective N -alkylation of an aza-glycine-containing peptide was successfully achieved, providing azapeptoids and N1,N2-dialkylated azapeptides in good conversions.…”

“…We envisioned that the difference in pK a values between acyl hydrazides and amides would enable selective functionalization of aza-amino acids embedded in peptides. 16 On-resin chemoselective N-alkylation of an aza-glycine-containing peptide was successfully achieved, providing azapeptoids and N1,N2dialkylated azapeptides in good conversions. In addition to providing rapid and easy access to underexplored peptidomi- metics, such late-stage transformations 17 significantly simplify the rapid generation of compound libraries.…”