Protein-protein interactions (PPIs) are implicated in virtually all cellular processes, from signal transduction to gene regulation, cell proliferation and apoptosis. Many diseases, including various forms of cancer, arise from or depend upon aberrantly misregulated PPIs. Chemical agents capable of targeting PPIs with high potency and selectivity can thus provide invaluable tools for chemical biology and drug discovery but the development of such agents has represented a fundamental challenge. This seminar will provide an overview of strategies introduced by our laboratory for directing the biosynthesis, evolution, and selection of genetically encoded macrocyclic peptides as modulators of protein-protein interactions. By integrating synthetic and biosynthetic tools, these methodologies enable the generation of ‘Macrocyclic Organo-Peptide Hybrids’ (MOrPHs), in which ribosomally derived peptides are cyclized by means of non-peptidic linkers and/or genetically encoded unnatural amino acids. These ‘natural product-inspired’ macrocycles combine a high degree of functional complexity within a conformationally constrained architecture, providing attractive molecular scaffolds for targeting protein complexes. Our group has recently integrated these methodologies with high-throughput screening platforms for accelerating the discovery of bioactive MOrPHs from genetically encoded libraries of these compounds produced in bacteria. Representative applications of these strategies for the development of potent and selective inhibitors of protein-protein interactions implicated in cancer will be discussed.
