A flexible and unstructured conformation is often preferred for nonfouling polymers and protein-polymer conjugates, with PEG as the most successful example. In this talk, we ask the question of whether the secondary structures such as the a-helix of synthetic polypeptides, also known as poly(a-amino acid)s (PaAAs), could impact their antifouling and long circulation behaviors in vivo. By using the neutral poly(g-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)esteryl glutamates) (P(EG3Glu)s) as a model system, we show that the polymers adopting a rigid rod-like a-helical conformation can self-assemble more rapidly to produce denser adlayers, and generate significantly improved nonfouling surfaces compared to those flexible polymer analogues including the widely used antifouling polymer PEG. Next, we examined the helical conformation in the context of protein-polymer conjugates. Our results reveal that the conjugate L20K-IFN, interferon (IFN) modified with the helical polypeptide L-P(EG3Glu) shows improved binding affinity, in vitro antiproliferative activity, and in vivo efficacy compared to those modified with the unstructured polypeptide analogue DL-P(EG3Glu) or PEG. Moreover, L20K-IFN triggered significantly less antidrug and antipolymer antibodies than the other two. Taken together, out studies highlight an urgent necessity to systematically reassess the pros and cons of choosing unstructured polymers for protein conjugation. Furthermore, our results also lay the foundation for the development of next-generation biohybrid drugs based on helical synthetic polypeptides.

Investigation of the role of helix conformation in antifouling and low immunogenetic polypeptides

2019 Fall National Meeting

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