Two-Helix Supramolecular Proteomimetic Binders Assembled via PNA-Assisted Disulfide Crosslinking

Peptidic motifs folded in a defined conformation are able to inhibit protein-protein interactions (PPIs) covering large interfaces and as such they are biomedical molecules of interest. Mimicry of such natural structures with synthetically tractable constructs often requires complex scaffolding and extensive optimization to preserve the fidelity of binding to the target. Here, we present a novel proteomimetic strategy based on a 2-helix binding motif that is brought together by hybridization of peptide nucleic acids (PNA) and stabilized by a rationally positioned intermolecular disulfide crosslink. Using a solid phase synthesis approach (SPPS), the building blocks are easily accessible and such supramolecular peptide-PNA helical hybrids could be further coiled using precise templated chemistry. The elaboration of the structural design afforded high affinity SARS CoV-2 RBD (receptor binding domain) binders without interference with the underlying peptide sequence, creating a basis for a new architecture of supramolecular proteomimetics.