Boosting peptide half-life: enabling efficient generation of Fc-peptide conjugates

Therapeutic peptides constitute a valuable class of drug candidates due to their ability to modulate targets which are often considered 'undruggable' by traditional small molecule drugs. Nevertheless, many peptides suffer from extremely short plasma half-life which limit their therapeutic potential. The fusion of therapeutic peptides to the Fc region of IgG antibodies has emerged as a highly established and effective approach for prolonging the systemic half-life of peptides. These Fc-fusion compounds are produced using recombinant techniques, expressed as a single linear polypeptide chain. However, such recombinant approaches limit incorporation of non-proteinogenic features such as peptides with non-natural amino acids, unnatural cyclic peptides, or pharmaceutical oligonucleotides. These features can increase stability, improve biological activity, and offer unique chemical properties. Therefore, the development of novel methods for the generation of Fc-fusion proteins which allow incorporation of these non-proteinogenic components is desirable. This work reports a semi-synthetic strategy for generating Fc-peptide conjugates through the design, synthesis, and bioconjugation of functionalised disulfide re-bridging linkers. Using this approach, an Fc-peptide conjugate was generated displaying retained biological activity in vitro and prolonged circulation in vivo. This methodology allows the simple and efficient generation of Fc-peptide conjugates.