A Selection of Macrocyclic Peptides That Bind STING From an mRNA?Display Library With Split Degenerate Codons

Recent improvements in mRNA display have enabled the selection of peptides that incorporate non-natural amino acids, thus expanding chemical diversity macrocycles beyond what is accessible nature. Such libraries incorporated acids at expense natural by reassigning their codons. Here we report an alternative approach to expanded amino-acid preserves all 19 (no methionine) and adds 6 resulting highest sequence complexity reported date. We applied this 25-letter library select functional bind human STING, a protein involved immunoregulation. The STING-binding include 9-mer macrocycle with dissociation constant (KD) 3.4 nM, which blocks binding cGAMP STING induces dimerization. This generalizable alphabet 25 building blocks.