Genetically Encoded Fragment-Based Discovery from Phage-Displayed Macrocyclic Libraries with Genetically Encoded Unnatural Pharmacophores

Genetically encoded macrocyclic peptide libraries with unnatural pharmacophores are valuable sources for the discovery of ligands many targets interest. Traditionally, generation such employs “early stage” incorporation building blocks into chemically or translationally produced macrocycles. Here, we describe a divergent late-stage approach to starting from readily available material: genetically peptides. A diketone linchpin 1,5-dichloropentane-2,4-dione converts displayed on phage 1,3-diketone bearing peptides (DKMP): shelf-stable precursors Knorr pyrazole synthesis. Ligation diverse hydrazine derivatives onto DKMP that carries silent DNA-barcodes yields in which amino acid sequence and pharmacophore by DNA. Selection this library against carbonic anhydrase enriched macrocycles benzenesulfonamide nanomolar Kd. The methodology described manuscript can graft existing significantly increase value molecular discoveries.