Introducing Chemoselective Peptide Conjugation via <i>N</i>-Alkylation of Pyridyl-alanine: Solution and Solid Phase Applications

A novel chemoselective peptide conjugation via late-stage <i>N</i>-alkylation of pyridyl-alanine (PAL) in the solution and solid phase, namely, NAP, is demonstrated. The method constructs functionally diverse and highly stable <i>N</i>-alkylated conjugates with various peptides. Notably, conjugations in the solid phase offered a more economical process. The method can provide the opportunity for dual labeling along with a cysteine handle in a peptide chain. Finally, we showcased that the antiproliferative activities of the p53 peptide (MDM2 inhibitor) could be 2-fold enhanced via NAP conjugation with the RGD peptide (selective integrin binder).