Discovering Cyclic Peptides That Can Enter Cells to Target 'Undruggable' Proteins

Researchers synthesized a combinatorial library of cyclic peptides inspired by natural product structures and screened them for membrane permeability. Membrane-permeable scaffolds were identified through library deconvolution. Structure-permeability relationships were investigated using a combination of experimental permeability assays (including Caco-2 cell assays) and computational modeling. Side-chain diversification was tested to assess scaffold adaptability for building target-specific libraries.

Many high-value drug targets — especially protein-protein interactions involved in cancer, autoimmune diseases, and infections — are considered 'undruggable' because they require molecules too large for traditional drugs but too complex for standard peptides. Cell-permeable cyclic peptides bridge this gap. This methodology enables rapid discovery of scaffolds that can enter cells, greatly expanding the chemical toolkit available for drug design against these challenging targets.

Cyclic peptides are having a renaissance in drug discovery. Natural products like cyclosporine showed that cyclic peptides can be orally bioavailable and cell-permeable, but expanding beyond natural product scaffolds has been challenging. This systematic approach to discovering new permeable scaffolds opens a much larger chemical space for drug development. It represents a key advance in the field of macrocyclic drug design, which has since grown into a major pharmaceutical research area.

The study focused on identifying permeable scaffolds rather than demonstrating bioactivity against specific disease targets. Permeability was measured primarily in cell-based assays (Caco-2), which may not fully predict in vivo behavior. Oral bioavailability and metabolic stability were not assessed. The approach identifies passive permeability but does not address active transport or efflux mechanisms that affect drug delivery in vivo.