Zwitterionic Peptide Fusion Proteins for Therapeutic and Protective Applications

Abstract

De novo design of peptide-based materials has become a common approach to introduce desirable properties into protein therapeutics. However, limited peptide-based technologies are capable of increasing the circulation time of and reducing the anti-drug antibodies (ADAs) of protein therapeutics as ADAs have been shown to reduce the circulation time and efficacy of many protein drugs following repeated administrations. Previous studies have shown the effective resistance of zwitterionic materials to non-specific protein adsorption. Zwitterionic materials such as polycarboxbetaine (pCB) are shown to be non-immunogenic. Glutamic acid (E) and lysine (K) containing zwitterionic peptides, which mimic protein surfaces, can be considered as the peptide version of PCB polymers, and exhibit similar resistance to non-specific protein adsorption. Here we develop a novel zwitterionic peptide fusion protein platform for therapeutic applications. This unique peptide design with the zwitterionic EK motif takes into account the chemical, physical, and biological properties of the resulting peptides such as high hydration and increased hydrodynamic size. We show that these peptides have long circulation, low immunogenicity, and retained their circulation profiles for multiple injections. In addition, we scale up the production and purification of organophosphate hydrolase (OPH) and its PCB conjugate for improved protection against chemical warfare nerve agents.