Understanding the Role of Zwitterionic Polymers or Peptides in the Bioactivity of Conjugated or Fused Proteins

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Nontechnical: Stabilizing protein-based therapeutics without sacrificing biological activity is a major challenge in the delivery of protein drugs. Conjugation with poly(ethylene glycol) (PEG) or PEGylation has been widely used to increase protein stability, but often accompanies an unwanted detrimental effect on protein bioactivity. At present, many polymer-protein conjugates suffer significant bioactivity loss. Zwitterionic materials are a promising alternative for preserving the bioactivity of conjugated proteins. The objectives of this work are to gain a fundamental understanding of the role of biomaterials in protein bioactivity when these biomaterials are conjugated to proteins and to develop new conjugates with improved stability, but minimum bioactivity loss. The success of this work will provide a fundamental understanding of the interactions of biomaterials with biomolecules and macromolecules at the molecular level and guide the design of new protein-conjugates for practical applications. The PI will recruit undergraduate students from underrepresented groups through established local programs and provide multidisciplinary research projects to graduate students, undergraduate students and high school students. The PI will promote the field of zwitterionic materials through organizing international conferences, editing journal special issues and promoting international collaborations. Technical: Conjugation with poly(ethylene glycol) (PEG) or PEGylation has been widely used to increase protein stability, but often accompanies an unwanted detrimental effect on protein bioactivity. The objectives of this work are to gain a fundamental understanding of the role of biomaterials in the bioactivity of polymer (or peptide)-protein conjugates and to develop new conjugates with improved stability, but minimum bioactivity loss. Through this work, it will be demonstrated that conjugation with zwitterionic polymers (or zwitterlation) or alternating-charge EK peptides (or EKylation) is better than PEGylation to retain protein bioactivity. In this work, several new biomaterials of different architectures, different types, and well-defined lengths will be used. Interferon (IFN)-alfa-2a will be used as a model protein for this fundamental study since the bioactivity of PEGylated (IFN)-alfa-2a is only 7% of its native form. This work employs state-of-the-art biomaterials and protein conjugation methods to solve one long-standing issue, i.e., significant bioactivity loss after PEGylation, particularly for large binding targets. The PI will recruit undergraduate students from underrepresented groups through established local programs and provide multidisciplinary research projects to graduate students, undergraduate students and high school students. The PI will promote the field of zwitterionic materials through organizing international conferences, editing journal special issues and promoting international collaborations.