RUI: Combinatorial Synthesis of Protein-Polymer Conjugates by Post-Polymerization Modification of Side-Chain Reactive Polymers

Non-technical description

Life as we know it would not exist without proteins. Proteins perform functions as wide-ranging as transporting oxygen through the body to recognizing and neutralizing invading microorganisms. Scientists have sought to harness the precise and exquisite functions of proteins to solve a variety of challenges in human health, such as by designing protein drugs that can diagnose and treat disease or by designing new protein scaffolds as part of engineered tissues.

Recently, researchers have recognized the power of using chemistry to augment or tailor the functions of proteins by modifying proteins with synthesized molecules. For example, large molecules known as polymers can be linked by chemical bonds to proteins in order to increase the stability of the protein or to tether drug molecules to the protein to create better therapeutics.

The goal of this project is to develop a fundamentally new approach for linking proteins to polymers. This approach will improve the efficiency of preparing protein-polymer conjugates (proteins linked to polymers through chemical bonds) for a wide range of applications, including drug delivery. The work will allow the structures of the protein-polymer conjugates to be easily tailored to the needs of specific applications without having to start from scratch.

Finally, polymer structures that are degradable in the human body can be coupled to proteins using this method, which is critical for translation to the clinic. To demonstrate the utility of this method, proteins that target cancer cells will be coupled to polymers for the development of new therapeutic structures. The principle investigator will conduct this work in collaboration with a diverse group of undergraduate women to inspire future generations of women researchers.

Further, the proposed research will be conducted in an undergraduate organic chemistry laboratory to offer cutting-edge research opportunities to a larger population of women. The principle investigator will also invite graduate students and postdoctoral scholars from nearby research universities to work together to teach undergraduate chemistry courses as a means to train the next generation of college faculty in best pedagogical practices in higher education.

Technical description

Protein-polymer conjugates couple the exquisite and precise functions of proteins with the wide-ranging functionality of synthetic polymers. These bioconjugates can be used to address important challenges in biotechnology and medicine such as the diagnosis and treatment of disease or engineering new tissues. Protein-polymer conjugates are generally synthesized by polymerizing monomers from protein initiators, termed grafting-from, or by coupling polymers containing a single reactive site at the chain end to specific amino acids on proteins, termed grafting-to.

Grafting-from requires that the monomer be water soluble and compatible with the protein structure; these requirements limit the range of chemical functionality that can be incorporated into the structure. Grafting-to suffers from low coupling efficiencies due to the need for two large molecules to react at a single site. In both approaches, new polymer structures must be synthesized each time new bioconjugate structures are desired.

This NSF project seeks to directly address these limitations by investigating side-chain reactive polymers for the modular and combinatorial synthesis of protein-polymer conjugates. The proposed work will use a post-polymerization modification strategy to synthesize hydrophilic, side-chain reactive polymers that can be efficiently conjugated to proteins through either amine-activated ester or thiol-maleimide reactions.

Side-chain and chain-end reactive polymers will be directly compared to establish side-chain reactive polymers as an alternative to terminally reactive polymers. Side-chain reactive polycarbonates will also be explored for the synthesis of degradable protein-polymer conjugates. The work proposed here will demonstrate efficient, combinatorial routes for protein-polymer-drug conjugate synthesis as well as contribute to the collective understanding of how macromolecular structure influences the function of protein-polymer conjugates.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.