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

The takeaway

Researchers developed a method to rapidly identify cell-permeable cyclic peptide scaffolds from combinatorial libraries, revealing that many novel structures beyond known natural products can passively cross cell membranes.

Novel permeable scaffolds beyond natural products
The study demonstrated that many cell-permeable cyclic peptide structures exist beyond those found in nature, and they can be rapidly identified using combinatorial synthesis and screening.

What the researchers found

Using a combinatorial library approach with synthesis and deconvolution, researchers identified multiple geometrically diverse cyclic peptide scaffolds with good to excellent passive cell permeability. Experimental and computational analysis of structure-permeability relationships revealed specific structural and conformational factors governing passive membrane diffusion among cyclic peptide diastereomers.

Critically, single-point side-chain diversifications of one scaffold demonstrated that permeability could be maintained while varying the functional groups — meaning these scaffolds can be adapted for bioactivity screening against different targets without losing cell permeability. The results show that the chemical space of cell-permeable cyclic peptides extends far beyond known natural products.

Why it matters

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.

How the study worked

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.

What this study cannot tell us

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.

How to read the evidence

This is a methodology and chemical biology study demonstrating proof of concept for discovering cell-permeable cyclic peptide scaffolds. It is well-executed but represents an early-stage platform technology rather than a therapeutic study.

When this study was published

Published in 2015 in the Journal of the American Chemical Society, this influential study helped establish the field of cell-permeable cyclic peptide drug design. The approaches developed here have been widely adopted and expanded upon.

The bigger picture

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.

Questions still open

Can these cell-permeable cyclic peptide scaffolds be developed into drugs against specific protein-protein interaction targets?
Do these scaffolds maintain permeability and stability in vivo for oral drug delivery?
How does the permeability of these synthetic scaffolds compare to the best natural product cyclic peptides like cyclosporine?

Common questions

What are cyclic peptides and why are they useful for drug design?

Cyclic peptides are peptides whose ends are joined to form a ring. This ring structure makes them more stable than linear peptides and can help them cross cell membranes. They are larger than typical drugs, which allows them to target flat protein surfaces and protein-protein interactions that small molecules can't effectively engage.

What makes some peptides able to enter cells while others can't?

This study found that specific structural and conformational features determine whether a cyclic peptide can passively diffuse through cell membranes. Factors like the peptide's shape, flexibility, and the arrangement of its building blocks all influence permeability. By understanding these rules, researchers can design new peptides that maintain cell entry ability while being customized for different drug targets.

Read the original research

Cell-permeable cyclic peptides from synthetic libraries inspired by natural products.

Journal of the American Chemical Society, 137(2), 715-21

View on PubMed ↗Publisher’s paper ↗

Citation

Hewitt, William M; Leung, Siegfried S F; Pye, Cameron R; Ponkey, Alexandra R; Bednarek, Maria; Jacobson, Matthew P; Lokey, R Scott. (2015). Cell-permeable cyclic peptides from synthetic libraries inspired by natural products.. Journal of the American Chemical Society, 137(2), 715-21. https://doi.org/10.1021/ja508766b