Discovering molecules that modulate protein-protein interactions is challenging, because the protein interfaces generally lack recognizable binding sites. Pennsylvania State University chemist Stephen Benkovic and colleagues have now developed a high-throughput technique that can identify rare inhibitors of these interactions. These molecules could be used as pharmaceutical lead compounds and probes of intracellular networks, Benkovic says, noting that Rigel Pharmaceutical in San Francisco has licensed the system for work in eukaryotes.

The researchers designed genetically encoded libraries of small cyclic peptides for expression in Escherichia coli. Cyclization renders the peptides resistant to cellular catabolism and simultaneously restricts conformational freedom, stabilizing the functional presentation of the peptide and potentially improving the affinity for target sites.1

The researchers monitored these molecules' effects on protein complexes that were fused with DNA-binding domains. Disrupting the protein-protein interaction permitted a promoter to direct the expression of three reporter genes and allow host cell growth....

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