Abstract:
Genetically-encoded (GE) libraries of proteins are a major source of discovery of “biological” drugs generating a $200 billion in sales in 2017. In Chemistry, GE libraries of 109 polypeptides made of 20 natural amino acids represent an orthogonal “raw material for organic synthesis”. Like canonical feedstock—petroleum-derived starting materials—GE-peptides are readily available but have limited structural diversity and practical utility. Like petroleum, peptides can be transformed to useful structures through multi-step organic synthesis. Departing from traditional diversification of low-functionality, achiral starting materials, we employ “late stage” modification of polar, functionality-rich, chiral molecules in water. Each transformation, when optimized, can routinely convert billion starting materials to billion products at once.
I will focus on recent developments from our group that expands the use of GE-technologies to Organic Chemistry and Chemical Biology. (1) Drug discovery for “undruggable targets” necessitates new chemical scaffolds of large surface area that do not break down in aggressive proteolytic environment encountered in serum or GI-tract. Using GE-libraries of peptides as a starting material for multi-step organic synthesis, we produce GE-libraries of novel bicyclic architectures that exhibit remarkable stability to proteolytic degradation. (2) We show that libraries of phage-displayed peptides can tackle fundamental physical-organic questions such as substrate control of Wittig reactions. (3) We develop approaches to generation of GE-libraries of any chemicals not derived from peptides. As example, we constructed genetically encoded “liquid glycan arrays (LiGA)”. LiGA is a reagent that can be combined with proteins, cells or tissues, inorganic materials, such as ice and safely injected into animals. Simple DNA sequencing then uncovers glycan-binding preferences of said proteins, cells, tissues, materials (ice) or various immune cells and organs in live animals.
Bio:
Ratmir Derda received his undergraduate degree in Physics from Moscow Institute of Physics and Technology in 2001, Ph.D. in Chemistry from the University of Wisconsin-Madison in 2008, under the supervision of Laura Kiessling, and postdoctoral training at Harvard University under the supervision of George Whitesides and Donald Ingber. He joined University of Alberta in 2011 as an Assistant Professor in Chemistry and was promoted to Associate Professor in 2017. In 2017 he founded 48HourDiscovery INC to translate genetically-encoded libraries and other technologies developed in Derda Group. His notable awards include Melanie O'Neill Young Investigator Award in Biological Chemistry (2018), David Gin New Investigator Award in carbohydrate chemistry from American Chemical Society (2017), Rising Star in Chemical Biology from the International Chemical Biology Society (2016); Young Investigator Award from the Boulder Peptide Society (2014); Gold Medal at the XXIX International Chemistry Olympiad (1997).