Genetically-encoded libraries of peptide derivatives

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The focus of my research program is synthesis and application of genetically-encoded libraries of organic molecules derived from peptides. We employ them for discovery of binding ligands for pharmaceutically challenging targets and molecules with unique molecular-recognition properties.***The proposed work aims to fulfill the increasing need for new chemical entities (NCE) with drug-like properties and to provide innovative technology for the discovery of therapeutic molecules. Chemically-modified peptides are a promising class of such candidates. Due to their small size, peptide derivatives can have tissue permeability akin to that of small molecules, while genetic selection allows for rapid discovery and optimization of these molecules. In the 1st cycle of NSERC DG, my lab developed a platform technology for genetically-encoded discovery of peptide derivatives. It is based on phage-displayed peptide libraries that are modified through multi-step, site-specific organic reactions. Using our 2nd cycle of NSERC DG, we will advance both synthesis and utility of GE-libraries.***Aim 1 will develop new chemical strategies that convert linear, genetically-encoded peptides displayed on phage to bicyclic structures. We use peptides displayed on phage as starting materials for organic synthesis. If the chemical reaction does not destroy the phage, synthesis can proceed for multiple steps and yield products that are genetically-encoded. The products can be selected and identified by their DNA tag, or amplified to re-generate the starting materials. To improve the lifetime of such molecules in circulation, we will graft ligands for albumin onto this library and select macrocycles with potent albumin binding capacity. This research will provide new strategies for accelerated early lead discovery in academic and industrial labs.***Aim 2 will discover reactions that target unique subtypes of peptide sequences: for example certain peptide sequences that have turns are most likely to react in a cyclization reaction. Typically, discovery of new reactions requires testing of a vast number of peptide sequences. We will accelerate discovery of such reactions using libraries of ~109 diverse peptides displayed on phage and design probes that covalently tag only peptides that underwent the desired reaction (here: cyclization) and permit their separation from the library. The proposed work represents a significantly new approach to reaction methodology.***Access to vast GE-libraries of molecules enables a risky yet exciting fundamental project that aim to discover molecules with functional properties that are difficult to predict by rational structural design. Aim 3 describes application of these libraries to find new light-responsive ligands that trigger autocatalytic processes, such as ice nucleation and mimic natural ice-nucleating proteins in one conformation (cis) but not in the other (trans).***