Abstract

Genetically encoded peptide libraries are at the forefront of de novo drug discovery. The RaPID (Random Nonstandard Peptides Integrated Discovery) platform stands out due to the unique combination of flexible in vitro translation (FIT) and mRNA display. This enables the incorporation of non-canonical amino acids, improving chemical diversity and allowing macrocyclisation of the peptide library. The resulting constrained peptides are valued for their strong binding affinity and stability, especially in the context of protein-protein interactions. In response to SARS-CoV-2, the causative agent of the COVID-19 pandemic, the RaPID system proved valuable in identifying high-affinity ligands of viral proteins. Among many peptide ligands of SARS-CoV-2 spike and main protease (M^pro), several macrocycles stand out for their exceptional binding affinities. Structural data showcases distinct binding modes in complex with the receptor-binding domain (RBD) of the spike glycoprotein or the catalytic active site of M^pro. However, translating these in vitro findings into clinical applications remains challenging, especially due to insufficient cell permeability.