Many of nature's most potent peptides aren't straight chains but rings. Microbes, plants and animals have evolved cyclic peptides for defence and competition, and they've inspired a whole field of drug design.
Why rings?
- Resistance to digestion: many enzymes that break down peptides attack the ends of the chain. A ring has no free ends.
- A pre-organised shape: a ring limits flexibility, so the molecule spends more time in its active shape and binds more tightly.
- Membrane permeability: some cyclic peptides can hide their polar groups and slip through cell membranes, which most linear peptides can't do.
Famous examples
Cyclosporin A
A cyclic peptide of 11 residues made by the soil fungus Tolypocladium inflatum. It suppresses the immune system and transformed organ transplantation in the 1980s. It's also unusual because it can be absorbed when taken by mouth. Its N-methylated backbone helps it cross membranes, which has made it a model for designing peptides that get into cells.
Gramicidin S
A cyclic decapeptide from the bacterium Brevibacillus brevis, discovered by Georgy Gause and Maria Brazhnikova in 1942. It was used on wounds during the Second World War and is still studied as a model antimicrobial.
Daptomycin and the polymyxins
Cyclic lipopeptides, rings with a fatty tail attached, that disrupt bacterial membranes. Both are important antibiotics for serious resistant infections.
Cyclotides
Plant peptides of about 30 residues, held together by a head-to-tail ring plus three interlocking disulfide bonds in a "cyclic cystine knot". They're extraordinarily stable against heat, acid and enzymes, and researchers use them as scaffolds to carry other active sequences.
Lessons for design
Natural cyclic peptides have taught chemists several strategies now used routinely: head-to-tail cyclisation, disulfide and thioether bridges, hydrocarbon "staples", N-methylation and D-amino acids. Combined with display technologies, these methods let researchers create cyclic peptides against targets that nature never made one for.
Related articles
- Antimicrobial peptides: an ancient defence against modern superbugs
- Display technologies: searching billions of peptides at once
- From lab to licence: how peptide medicines are developed
Sources and further reading
- Gause GF, Brazhnikova MG. Gramicidin S and its use in the treatment of infected wounds. Nature 1944;154:703. doi:10.1038/154703a0
- Craik DJ et al. Plant cyclotides: a unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif. J Mol Biol 1999;294:1327–1336. doi:10.1006/jmbi.1999.3383 · PMID: 10600388
- Craik DJ, Fairlie DP, Liras S, Price D. The future of peptide-based drugs. Chem Biol Drug Des 2013;81:136–147. doi:10.1111/cbdd.12055 · PMID: 23253135
- Yamagishi Y et al. Natural product-like macrocyclic N-methyl-peptide inhibitors against a ubiquitin ligase uncovered from a ribosome-expressed de novo library. Chem Biol 2011;18:1562–1570. doi:10.1016/j.chembiol.2011.09.013 · PMID: 22195558