Expanding the Chemical Space of Phage isplay

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Proteins play important roles in complex human biology and biological malfunction. The use of chemical tools in biology allows scientists to control of the behavior of specific proteins. Phage display is a technique used to study protein?protein, protein?peptide, and protein?DNA interactions. Phage display uses bacteriophages (viruses that infect bacteria) to connect proteins with the genetic information that encodes them. Phage display has been limited to the creation of peptides that occur in nature. This project expands the capabilities of peptides that can be of use in controlling protein behavior by providing a new path to making peptides from amino acids that have been chemically altered. Students from Roxbury Community College and high school students from the Greater Boston area are actively engaged in the research efforts to use chemistry to solve biological challenges. Importantly, this project includes detailed biochemical and structural studies of the ligand-protein binding mechanisms that may yield new guiding principles for protein recognition by synthetic molecules and eventually, new treatments for biological malfunction. With this award, the Chemistry of Life Processes Program is funding Professor Jianmin Gao at Boston College to develop chemically-modified phage libraries and explore their potential for targeting proteins that have eluded small molecules and natural peptides. Phage display, as a genetically encoded screening platform, has largely limited the displayable molecules to peptides comprising proteinogenic amino acids, which often fall short in generating high-affinity probes and inhibitors for proteins that do not have a well-defined recognition region. Dr. Gao overcomes this limitation by modifying phage-displayed peptides to present unnatural functionalities. Clever use of biocompatible and chemoselective reactions for phage modification is expected to yield novel phage libraries, with each peptide member carrying two distinct designer functionalities. Building on this innovative technology for phage modification, Dr. Gao and his research team seek to develop a "ligand maturation" protocol that allows facile conversion of low-affinity ligands into potent binders of the target protein in the form of ligand-peptide 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.