University of Alberta
Genetically-Encoded Discovery of Bicyclic Inhibitors for Nodal
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. 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. We show that libraries of phage-displayed peptides can tackle fundamental physical-organic questions such as substrate control of Wittig reactions. To permit building libraries with unnatural chemotypes / fragments / pharmacophores, I will describe new chemical strategy to late-stage functionalization of macrocyclic peptide libraries displayed on phage.