Novel Synthetic Methods for Stabilization of Peptide Nanotubes

Hollow tubular structures, also known as nanotubes, are a valuable architecture with applications spanning electronic sensors, structural materials, membrane channels, and payload delivery. As such, chemical, biological, and materials scientists are invested in developing artificial tubular structures for these applications. The cyclic peptide nanotube (cPNT) is an attractive organic tubular structure composed of cyclic peptide subunits due to characteristics like excellent aqueous solubility, ample functionalization potential, and low toxicity in biological systems. They are composed of identical medium-sized cyclic peptides that adopt a flat conformation allowing them to stack on top of one another held together by intermolecular H-bond interactions. However, H-bonds are weak intermolecular interactions and sensitive to external stressors, such as H-bond competitors or polar solvents, negatively impacting the prolonged stability of such structures. This research program will investigate new methods to stabilize peptide nanotube architectures using covalent tethers with a long-term vision of developing peptide architectures as customizable tools for molecular imaging and payload delivery applications. The following are short-term objectives on route to these outcomes. 1) Installing orthogonal functional groups in different locations along cyclic peptide subunits to facilitate a covalent cross-linkage between neighbouring subunits. Peptide backbone linkages will replace one traditional amide bond with an amide bond isostere bearing orthogonal functionality to facilitate a connection leaving external side chains available for application focused modifications. Peptide side chain linkages utilize the accessible peripheral side chain functional groups to facilitate connections. 2) Redesigning peptide nanotube architecture by replacing cyclic peptide subunits with a small molecule tether and linear peptide subunits. The revamped architecture features an integrated signaling source, tunable nanotube diameter and surface polarity, and controllable nanotube length. New chemical entities developed from these objectives will be rigorously evaluated for stability and cell internalization to develop an extensive knowledge-base in relation to nanotube attributes (diameter, length, intermolecular spacing) guiding nanotube design towards ideal molecular imaging and payload delivery vehicles. My research merges medicinal chemistry, organic chemistry, and radiochemistry together using peptide chemistry as our common theme. Trainees participating in this multidisciplinary area develop skills relating to organic synthesis, peptide synthesis, radiosynthesis, and biological assays that translate to marketable skills for future opportunities in industry and academia.