Advanced Bioconjugation Technologies for Site-selective Protein Modification
Name of applicant
Katrine Qvortrup
Institution
Technical University of Denmark
Amount
DKK 4,392,700
Year
2018
Type of grant
Semper Ardens: Accelerate
What?
Bioconjugation is a strategy that links a protein with different substrates: enabling modulation of the properties of proteins in a desired direction. An effective conjugation technology has to control both the location and the number of molecules being incorporated in the protein. This imperative is of substantial importance, and development of new selective methodologies is crucial to the further advancement of bioconjugation and its applications in numerous fields like medicine and materials. In the current project, novel approaches for the preparation of well-defined conjugates will be developed. Thus, the knowledge gained from this work should be of considerable value in the design and production of bioconjugates with specific biological/chemical profiles.
Why?
Synthetically modified proteins (bioconjugates) can have diverse functionalities, such as storing energy of sunlight, probing complex biological processes, and targeted drug delivery. Traditional strategies rely on the side-chain reactivity of one amino acid in a wild-type protein. A typical protein contains 200-300 amino acids and with only 20 proteinogenic amino acids available, these strategies will unavoidably be associated with non-selectivity resulting in heterogeneous product mixtures (that is, variation in the number of molecules incorporated and their locations on the protein), limits their widespread application. This project will address this problem, by developing novel approaches for 'site-selective' conjugation, hereby improving their application in medicine and materials.
How?
Each bioconjugation technology will be identified through peptide library synthesis and reactivity screening with electrophilic partners. Peptides will be synthesized using well-established solid-phase synthesis strategies, which will allow us to synthesize and test reactivity of a broad range of peptides with a variety of suitable electrophiles in a short time. After successful development of the conjugation strategies, we plan to testify the full potential of the technologies by demonstrating the use in a real biomedical application. As a proof-of-concept, we will demonstrate the use of the novel conjugation strategies for attachment of the linker-drug component to the antibody in the preparation of antibody-drug conjugates for cancer treatment.