Synthesis of Branched Oxime-Linked Peptide Mimetics of the MUC1 Containing a Universal T-Helper Epitope

Our goal was to develop mimics of MUC1, highly immunogenic to induce an efficient immune response against the tumor‐associated form of MUC1, and sufficiently different from the natural antigen to bypass the tolerance barrier in humans. With the aim of obtaining a well‐defined peptide construct as a means of evoking the precise immune responses required in immunotherapy, we synthesized artificial mimics of the MUC1 protein composed of two MUC1 repeat units of inverse orientation and a universal T‐helper epitope. To synthesize these heteromeric peptide constructs, we followed a convergent approach using chemoselective ligation based on oxime chemistry. A stem peptide was first synthesized bearing two orthogonally masked aldehydes. After successive deprotection, two oxime bonds can be specifically generated. The proposed strategy proved to be concise and robust, and allowed the synthesis of the tri‐branched protein in a very satisfactory yield. The different constructs were tested for their ability to generate antibodies able to recognize the MUC1 protein. A stem peptide bearing two masked aldehydes such as 2 has been used as an effective synthon for building the branched oxime‐linked conjugate 1 from MUC1 tandem repeat sequences and a universal T‐helper epitope. This original tri‐branched construct induces antibodies which recognize a recombinant MUC1 protein.