Polypept(o)ides – Origins, synthesis, applications and future directions

Polypept(o)ides combine the stealth-like properties of polypeptoids such as polysarcosine (poly(N-methyl glycine), pSar) with the multifunctionality and intrinsic stimuli-responsiveness of synthetic polypeptides. This class of copolymers can be synthesized by controlled living ring-opening polymerization of the corresponding α-amino acid N-carboxyanhydrides (NCAs) and N-substituted glycine N-carboxyanhydrides (NNCAs). When the polymerization is performed under clean conditions, the resulting copolymers are characterized by high end-group fidelity and Poisson-like molecular weight distributions with dispersities below 1.2. While pSar might be able to tackle most of the current concerns of poly(ethylene glycol) (PEG), e.g., acute immune responses, the polypeptide part can provide a plethora of reactivity or functionality, allowing to tailor the polymer for specific tasks. In this review, we provide an overview on the origins of NCA polymerization and polypept(o)ides and provide a detailed overview on the last decade of research focusing on synthesis, characterization, and application. Arguably the biggest applicational progress for polypept(o)ides has been made in nanomedicine. Here, the remarkable combination of functionality, biocompatibility and a high degree of synthetic control has led to established protocols for the certified production of polypept(o)ides, which will enable the rapid clinical translation for the years to come.