"Genetically-Encoded Chemistry: Discovery of molecular interactions in vitro and in vivo"
Prof. Ratmir Derda, University of Alberta
Abstract: Genetically-encoded libraries (GEL) and DNA-encoded libraries (DEL) are increasingly used as tools that guide discovery of ligands or drug leads and solve general problems in molecular recognition. Phage display—the platform that inspired modern GEL and DEL—is one of a few technologies that permit discovery of molecular interactions in a complex milieu on the surface of cells and inside living organisms. Injection of phage libraries inside living animals and humans, known as “in vivo phage display” has been practiced using canonical peptide and antibody libraries made of 20 natural amino acids. Derda Lab bridges the power of GEL/DEL with organic synthesis to yield new classes of encoded libraries displayed on phage virion. Like canonical feedstock—petroleum-derived starting materials—phage-displayed peptides are readily available and can be transformed to useful structures through multi-step organic synthesis. “Late stage” modification of these GE libraries in water, when optimized, can routinely convert million to billion diverse starting materials to products at once. Alternatively, nascent phage virions bearing DNA barcodes can be used as prospectively-tagged support for synthesis of any structures. I will describe chemical and chemoenzymatic synthesis of complex glycans on phage virions. These glycan libraries, when displayed on phage are also amenable to in vivo display: they can be injected into living animals to identify the compounds that exhibit desired molecular recognition properties (e.g., interact with specific cell or organ).
1. Ratmir Derda and Simon Ng “Genetically-Encoded Fragment-Based Discovery (GE-FBD)”, Cur. Opin. Chem. Biol., 2019, 50, 128.
2. Arunika Ekanayake, et al., “Genetically Encoded Fragment-Based Discovery (GE-FBD) from Phage-Displayed Macrocyclic Libraries with Genetically-Encoded Unnatural Pharmacophores“, J. Am. Chem. Soc., 2021, 143, 14, 5497.
3. Jeff Wong, et al., “Genetically-Encoded Discovery of Proteolytically Stable Bicyclic Inhibitors of Morphogen NODAL“,Chem. Sci., 2021,12, 9694.
4. Mirat Sojitra, et al., “Genetically encoded multivalent liquid glycan array displayed on M13 bacteriophage“, Nat. Chem. Biol. 2021, 17, 806.