One Ring to Rule Them All

By Jason Socrates Bardi

A group of chemists at The Scripps Research Institute has recently announced that they have made the largest synthetic cyclic peptide ever—a ring of atoms composed of two separate peptides (chains of amino acids) joined together at the ends. 

Cyclic peptides are a popular class of compounds for both materials science research and for medical purposes because they provide a useful way of constraining the geometry of a peptide. Peptides are flexible molecules, and so those that exist in the chain form tend to twist around randomly in solution. In contrast, peptides forming a ring have more limited ability to twist into random conformations and instead tend to preserve a special arrangement of atoms, which can be used to target specific proteins or other molecules in the body that recognize this specific geometry.

In fact, many different drugs contain peptide ring structures or are derivatives of cyclic peptides—from antibiotics like penicillin and vancomycin to drugs like the immunosuppressant cyclosporin.

Given the utility of cyclic peptides, scientists have for years sought ways to make cyclic peptides and peptide-like compounds, and techniques for making peptide ring structures abound in synthetic chemistry. However, not all of them are easy to use, and there is still a need for convenient and cheap methods for producing cyclic peptides.

Associate Professor M.G. Finn and his colleagues set out to design just such a methodology. And when they were finished, they found they had made cyclic peptides of unprecedented size.

“It was a complete surprise,” says Finn.

One ring they made is composed of two identical 10-amino-acid peptides joined end-to-end to make a 76-atom ring. An even larger ring was formed by joining two identical 18-amino-acid peptides end-to-end to form a 124-atom ring. By comparison, the ring size of the cyclosporin—one of the largest existing synthetic cyclic peptides—is only 33 atoms.

How They Did It

The basis for creating the dimer rings was the copper-catalyzed azide-alkyne “click” reaction, which has been developed by Scripps Research investigators K. Barry Sharpless and Valery V. Fokin and their colleagues over the last several years. Sharpless is the W.M. Keck Professor of Chemistry at Scripps Research and a recipient of the 2001 Nobel Prize in Chemistry for some of his earlier work on chemical synthesis.

Click chemistry is a powerful and original protocol for organic synthesis that relies upon using energetic yet stable building blocks that react with each other in a highly efficient and irreversible spring-loaded reaction. The azide and alkyne blocks have emerged as the favorites of chemists around the world, because they are inert to most other molecules and reaction conditions, but become strongly and permanently bonded to one another when they are brought into close contact.

By attaching azides to one end of peptides and alkynes to the other end, Finn and his colleagues set out to use click chemistry to make their cyclic peptides. The real advantage of this technique, says Finn, is that it lends itself to easy and convenient methodology using a solid support phase and copper catalysts.

When they were done, though, Finn and his colleagues found they had created the largest peptide ring structure ever synthesized. They had intended to make single ring cyclic peptides—visually something like Ouroboros, the snake that is biting its own tail. Only when they ran the reaction and isolated the products, they found they had instead created double-ring peptides—what might be called a “Duoboros,” or two snakes, each biting the tail of the other.

But Finn and his colleagues had not built anything into the reaction to bias it towards the creation of dimer peptides. So why would the peptides form two-peptide chains instead of one? And why would they not form the other products that might be predicted if the process of joining the ends were random—products such as larger loops and catenanes (intercalated rings)?

Although the scientists have yet to completely understand the mechanism, the answer, says Finn, starts with the fact that the reaction requires two copper atoms to work, forcing the two peptide chains together and making the formation of double rings appropriate.

In the mean time, the scientists are continuing to explore the new methodology for making other cyclic molecules, including a cyclic peptide library, catenanes, and non-peptide cyclic structures for a variety of uses.

“Rings are very interesting things,” says Finn.

To read the article, “Head-to-Tail Peptide Cyclodimerization by Copper-Catalyzed Azide–Alkyne Cycloaddition” by Sreenivas Punna, Jane Kuzelka, Qian Wang, and M. G. Finn, go to: http://dx.doi.org/10.1002/ange.200461656

Send comments to: jasonb@scripps.edu

This simple representation shows the side chains of the largest synthetic cyclic peptide ever made, a 124-atom ring recently described in a paper by Associate Professor M.G. Finn and his colleagues. Click to enlarge.