Revealing the Potential of a Chimaera: a Peptide‐Peptide Nucleic Acid Molecule Designed To Interact with the SARS‐CoV‐2 Nucleocapsid Protein

Abstract Numerous RNA‐binding proteins have modular structures with folded domains and intrinsically disordered regions, making their atomic characterization difficult. This severely limits the investigation of their modalities of interaction as well as the evaluation of possible ways to interfere with this process. We report herein a rational strategy for the design and synthesis of a ligand able to interfere with the protein function, monitoring the interaction through solution nuclear magnetic resonance spectroscopy. Our approach employs a chimaera composed of two different fragments, a peptide and a peptide‐nucleic acid, allowing to incorporate in the resulting molecule key features to address RNA‐protein interactions. Focusing on two constructs of the Nucleocapsid protein from SARS‐CoV‐2, the globular N‐terminal domain and a more extended one comprising also two flanking intrinsically disordered regions, we demonstrate the enhanced affinity of the designed peptide‐peptide nucleic acid chimaera for the protein compared to a related peptide lacking π–π stacking contributions within the chain. Furthermore, we emphasize the increasingly recognized relevant and synergistic role of the intrinsically disordered regions in protein‐ligand interaction.