Protein–protein
interactions represent a new class of exciting but challenging drug
targets, because their large, flat binding sites lack well-defined
pockets for small molecules to bind. We report here a methodology
for chemical synthesis and screening of large combinatorial libraries
of bicyclic peptides displayed on rigid small-molecule scaffolds.
With planar trimesic acid as the scaffold, the resulting bicyclic
peptides are effective for binding to protein surfaces such as the
interfaces of protein–protein interactions. Screening of a
bicyclic peptide library against tumor necrosis factor-α (TNFα)
identified a potent antagonist that inhibits the TNFα–TNFα
receptor interaction and protects cells from TNFα-induced cell
death. Bicyclic peptides of this type may provide a general solution
for inhibition of protein–protein interactions