Introducing\nChemoselective Peptide Conjugation via <i>N</i>‑Alkylation\nof Pyridyl-alanine: Solution and Solid\nPhase Applications

A novel chemoselective peptide conjugation via late-stage <i>N</i>-alkylation of pyridyl-alanine (PAL) in the solution and\nsolid phase, namely, NAP, is demonstrated. The method constructs functionally\ndiverse and highly stable <i>N</i>-alkylated conjugates\nwith various peptides. Notably, conjugations in the solid phase offered\na more economical process. The method can provide the opportunity\nfor dual labeling along with a cysteine handle in a peptide chain.\nFinally, we showcased that the antiproliferative activities of the\np53 peptide (MDM2 inhibitor) could be 2-fold enhanced via NAP conjugation\nwith the RGD peptide (selective integrin binder).