EAPSI: Creation of Libraries of Methylene Thioacetal Bridged Peptides for Ligand Discovery

Iqbal Emil S, Richmond VA

Investigators

Abstract

Numerous disease states are driven by anomalous protein-protein interactions. These interactions typically involve adhesive protein surfaces making large contacts that are hard to disrupt. The result is that traditional small molecule drugs cannot sufficiently break up these interactions; thus these interactions have been drugged "undruggable." In the past few decades, peptides have emerged as an alternative due to their large size are ability to interact with large surface contact area in protein-protein interactions. There are many well developed technologies for identifying potential peptide therapeutics, this work will focus on developing technology to expand the chemical diversity of peptides available in the most powerful technique: mRNA display. This work will be completed under the guidance of Dr. Hiroaki Suga at the University of Tokyo. Dr. Suga is a world expert in mRNA display and peptide ligand discovery whose expertise will prove invaluable for completion of the project. Many biologically relevant peptides and proteins contain macrocycles to stabilize tertiary structures and protect against proteolytic degradation. Researchers have developed several macrocyclization techniques to create peptide mimics of biological structures, most notably: lactam bridging, Grubbs metathesis, dibromoxylene cyclization, azide-alkyne "click" chemistry, and head-to-tail cyclization to name a few. Many of these peptides have even moved to clinical trials in several disease models. Though all these methods create large macrocyclic peptides, all require a bridging moiety of substantial size. Evolutionarily pressures have optimized biological macrocycles to create many surface contacts in ligand-protein interactions; large bridging moieties can sufficiently disrupt this optimized network negating any benefits of stability conferred. This project will focus on integrating a method of methylene bridge disulfide creation into the peptide ligand discovery platform of mRNA display. This platform is far and away the most powerful method of peptide ligand discovery, capable of simultaneously creating and screening 1013 unique peptides. Because the methylene bridge cyclization introduced in the proposed work is only a single carbon, this method will be offer a tool to create large libraries of peptides having a minimally disrupting bridging moiety. This technology will be initially applied to a screen for trypsin inhibitors and will ultimately be be added to the growing toolkit for identifying peptide ligands inhibiting protein-protein interactions. This award, under the East Asian and Pacific Summer Institutes program, supports summer research by a U.S. graduate student and is jointly funded by the NSF and the Japan Society for the Promotion of Science.