Chemical labeling strategies using biomolecule-compatible, nonaqueous media

2023. NIH MIRA project summary abstract Title: Chemical labeling strategies using biomolecule-compatible, nonaqueous media Abstract: Among many classes of chemical tools devised to date, protein bioconjugation technologies have proven valuable in a wide variety of contexts such as preparation of therapeutic agents and study of disease mechanism The last decade has witnessed a substantial advance in bioconjugation technologies, although challenges of selective and efficient labeling have not been completely addressed to date for many of the 20 canonical amino acids. Our research program tackles the longstanding issues of selective bioconjugation of unactivated amino acids by identifying nonaqueous media suitable for both biomolecules and organic chemistry reactions, which has not been actively pursued to date and is innovative from the applicant’s point of view. Our long-term goal is to develop bioconjugation methods selectively targeting amino acids that were inaccessible by previous approaches in aqueous media. Our overall objective in this application is to discover chemical methods for chemoselective functionalization of hydrophobic, unactivated, and less abundant amino acids, offering higher chance of site-specific modification due to their lower natural abundance and less surface exposure. Our central hypothesis is that nonaqueous media can be compatible with proteins and induce chemical reactions that were not achievable in aqueous medium. The rationale for the proposal is that development of novel bioconjugation methods is expected to become facile by gaining access to a large number of synthetic methodology literature that often relies on nonaqueous media. The proposed research is significant because it is expected to provide a chemical tool to target amino acid residues that were inaccessible by the traditional methods and to provide a new paradigm to create bioconjugates.