Arunika received her Ph.D. in Chemistry from the University of Southern California in sunny Los Angeles, where she worked on the proteome-wide discovery of covalent ligands and their targets, including covalent kinase inhibitors, at the Loker Hydrocarbon Research Institute. She then moved to the University of Alberta in sunnier Edmonton, Alberta for her postdoctoral fellowship, where she is currently a MITACS Canada postdoctoral fellow in Professor Ratmir Derda's group.

Arunika's work in the Derda research group involves genetically encoded chemistries to explore the reaction space of millions to billions of substrates in parallel. One of the main goals of her postdoctoral work is genetically encoded fragment-based discovery from phage-displayed macrocyclic libraries with genetically encoded unnatural pharmacophores, and Arunika is very excited to share the current developments of this project at APS Whistler 2022, Peptide Science at the Summit.

Genetically encoded fragment-based discovery, GE-FBD, is a promising approach for the selection of ligands and drug leads from existing GE libraries displayed on phage, DNA, or mRNA. GE-FBD starts with a fragment that interacts with a known site of the target protein but often with low potency and specificity. Covalent incorporation of unnatural fragments or "pharmacophores" into conventional peptide libraries expands the chemical space and facilitates the discovery of molecules with favorable properties not offered by the fragments alone.

This strategy can be applied to both linear and cyclic peptide libraries, using pharmacophores that have covalent as well as non-covalent reactivities towards target proteins. Since cyclic peptides alleviate several caveats presented by linear peptides, macrocyclization strategies that enable the installation of pharmacophores or other chemical moieties are highly desirable. Traditionally, the generation of GE-FBD libraries employs "early-stage" incorporation of unnatural building blocks into the chemically or translationally produced macrocycles.

This talk will describe a divergent late-stage modification approach to such libraries starting from readily available starting material: genetically encoded phage-displayed libraries of peptides. Converting these phage-displayed peptides to 1,3-diketone bearing macrocycles provides a shelf-stable precursor for further functionalization with hydrazine through a well-established Knorr-pyrazole synthesis reaction. Ligation of diverse hydrazine derivatives onto diketone macrocyclic peptide libraries displayed on a phage that carries silent DNA barcodes enables genetic encoding of these post-translational chemical modifications. These libraries can be applied against "undruggable" protein targets to discover ligands with improved affinity and specificity.