title: Bicyclic peptide ligands pulled out of cysteine-rich peptide libraries.
abstract: Bicyclic peptide ligands were found to have good binding affinity and target specificity. However, the method applied to generate bicyclic ligands based on phage-peptide alkylation is technically complex and limits its application to specialized laboratories. Herein, we report a method that involves a simpler and more robust procedure that additionally allows screening of structurally more diverse bicyclic peptide libraries. In brief, phage-encoded combinatorial peptide libraries of the format X(m)CX(n)CX(o)CX(p) are oxidized to connect two pairs of cysteines (C). This allows the generation of 3 × (m + n + o + p) different peptide topologies because the fourth cysteine can appear in any of the (m + n + o + p) randomized amino acid positions (X). Panning of such libraries enriched strongly peptides with four cysteines and yielded tight binders to protein targets. X-ray structure analysis revealed an important structural role of the disulfide bridges. In summary, the presented approach offers facile access to bicyclic peptide ligands with good binding affinities.
authors.affiliation: Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Shiyu
authors.initials: S
authors.lastname: Chen
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Rentero Rebollo
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Buth
authors.forename: Julia
authors.initials: J
authors.lastname: Morales-Sanfrutos
authors.forename: Jeremy
authors.initials: J
authors.lastname: Touati
authors.forename: Petr G
authors.initials: PG
authors.lastname: Leiman
authors.forename: Christian
authors.initials: C
authors.lastname: Heinis
mesh_terms: D000478:Alkylation; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D020650:Combinatorial Chemistry Techniques; D003460:Crystallization; D003545:Cysteine / Q000737:chemistry*; D004220:Disulfides; D004591:Electrophoresis, Polyacrylamide Gel; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry*; D014961:X-Ray Diffraction
chemical_list: D000596:Amino Acids; D001643:Bridged Bicyclo Compounds; D004220:Disulfides; D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D003545:Cysteine