The Potential of Peptoid Macrocycles to Stabilize G-quadruplexes for Cancer Inhibition

A major challenge in cancer therapeutics is poor selectivity when targeting protein-based pathways. One emerging strategy is to target nucleic acid structures, such as G-quadruplexes (G4s), to regulate oncogene expression. G4s are distinctive noncanonical nucleic acid structures formed by guanine-rich DNA sequences. Four guanine bases hydrogen bond through Hoogsteen interactions to form planar G-tetrads, which stack to create the G4 structure. G4s can act as transcriptional roadblocks at key genomic sites, including oncogenes like c-MYC. While G4s can be unwound, stabilizing them has been shown to downregulate transcription, inhibit cell proliferation, and limit tumor growth. One promising approach for G4 stabilization is the use of peptoids - poly-N-substituted glycines. Their abiotic backbone provides peptoids with proteolytic resistance, tunable side-chain diversity, and the ability to form macrocycles, allowing both specificity and cell permeability. These properties make peptoids advantageous over typical small molecules or peptide-based therapeutics. This research synthesizes cyclic tetrameric and hexameric peptoids with alternating proline residues designed to selectively stabilize a G4 in the c-MYC gene. Binding interactions and stabilization effects are characterized using Circular Dichroism (CD) spectroscopy and NOESY NMR. To date, the use of peptoids as G4 stabilizers remains largely unexplored. This project aims to fill that gap, offering a novel approach to targeted gene regulation in cancer.