Cell-Penetrating Cyclic and Disulfide-Rich Peptides Are Privileged Molecular Scaffolds for Intracellular Targeting

Peptides that have a head-to-tail cyclic backbone tend to be more stable than linear peptides, as do peptides that contain one or more cross-linking disulfide bond. Some of these cyclic and/or disulfide rich peptides have been reported to penetrate cells. These include peptides from a wide range of natural sources, including plants, spiders, crabs, and humans. In this review we describe the structures and biophysical properties of a selected set of such peptides that have been studied in our laboratories. We further describe how they can be engineered to enhance their stability and cellular uptake, and to fine-tune selective cell entry and activity toward intracellular therapeutic targets. Examples of targets described include intracellular protein–protein interactions implicated in cancer, intracellular malarial parasites and intracellular bacterial targets. In addition to the important advances being made with these nature-inspired peptides, the rapid strides in machine learning and artificial intelligence seen over recent years promise to accelerate the use of de novo design methods to produce peptides that are able to pass through biological membranes. We describe examples where such approaches have been used to design macrocyclic peptides and peptide–drug conjugates that can penetrate cell membranes and even have significant oral bioavailability in some cases.