Study yields more than a million new cyclic compounds, some with pharmaceutical potential

March 12, 2018 by Diana Yates, University of Illinois at Urbana-Champaign
University of Illinois chemistry professor Wilfred van der Donk and his colleagues developed a new method for generating large libraries of unique cyclic compounds. Credit: Don Hamerman

Researchers say they can now produce a vast library of unique cyclic compounds, some with the capacity to interrupt specific protein-protein interactions that play a role in disease. The new compounds have cyclic structures that give them stability and enhance their ability to bind to their targets.

The study, reported in the journal Nature Chemical Biology, also revealed that one of the newly generated compounds interferes with the binding of an HIV to a , an interaction vital to the virus's life cycle.

Most drug-discovery efforts focus on disease-inducing interactions in enzymes and proteins that involve classic "lock-and-key" mechanisms, said University of Illinois chemistry professor Wilfred van der Donk, a Howard Hughes Medical Institute Investigator who co-led the study with University of Southampton chemical biology professor Ali Tavassoli. "In most cases, small chemical drugs bind to cavities in enzymes, where the chemical reactions take place. By binding to these crevices, the drugs prevent the enzymes from working."

However, many disease processes involve that do not fit this model, van der Donk said.

"These have long been considered challenging because they do not involve such cavities. These protein-protein interactions often are made up of extended surfaces that can be difficult to inhibit with small molecules," he said.

Linear peptides also are problematic. They can be "floppy, like spaghetti, and therefore most of the time are in incorrect orientations to bind," van der Donk said. Cyclic molecules composed of one or more rings of are more stable and less susceptible to cellular enzymes that tend to chew off the ends of linear peptides. They are thus more likely to successfully bind to their targets.

In the new study, van der Donk and his colleagues made use of an they discovered from a bacterium that lives in the ocean.

"This enzyme's natural role is to make about 30 different cyclic proteins, and we tested whether it could make analogs of these natural products in Escherichia coli," van der Donk said. E. coli has been used as a drug-producing factory for pharmaceutical products.

The genetic sequences inserted into E. coli all coded for a series of amino acids recognized by the enzyme. By randomly adding specific amino acids to this "leader sequence," the team was able to generate a library of more than a million unique multicyclic proteins.

Tavassoli and his colleagues next screened this library in genetically engineered E. coli for proteins that could interrupt the binding of the HIV protein to its human host cell target.

"We engineered the genes of the E. coli strain such that its survival depended on disrupting the interaction between the human protein and an HIV protein," Tavassoli said. His team found three potential therapeutic agents. Further testing revealed that one of the three worked best. In a test tube and in cells, the compound bound to the human protein, stopping the HIV protein from interacting with it.

This drug agent likely will not be used therapeutically, however, as it may have toxic side effects at high doses as a result of its interaction with the human protein, the researchers said.

"The real advance here is the ability to generate libraries of millions of potentially therapeutic agents," Tavassoli said. "These could be screened to identify inhibitors of other disease-related processes, which is where its real potential lies."

Explore further: Measuring molecular interactions

More information: Xiao Yang et al, A lanthipeptide library used to identify a protein–protein interaction inhibitor, Nature Chemical Biology (2018). DOI: 10.1038/s41589-018-0008-5

Related Stories

Measuring molecular interactions

February 1, 2018

ETH Zurich researchers have used a new approach to discover previously unknown interactions between proteins and small metabolic molecules in bacterial cells. The technique can also be used to test the effect of medications.

Study: Odd biochemistry yields lethal bacterial protein

January 22, 2013

While working out the structure of a cell-killing protein produced by some strains of the bacterium Enterococcus faecalis, researchers stumbled on a bit of unusual biochemistry. They found that a single enzyme helps form ...

Completing the drug design jigsaw

October 5, 2017

A powerful new way of analysing how drugs interact with molecules in the body could aid the design of better treatments with fewer side-effects.

Recommended for you

New battery gobbles up carbon dioxide

September 21, 2018

A new type of battery developed by researchers at MIT could be made partly from carbon dioxide captured from power plants. Rather than attempting to convert carbon dioxide to specialized chemicals using metal catalysts, which ...

Scientists solve the golden puzzle of calaverite

September 21, 2018

Scientists from Russia and Germany have shed light on the crystalline structure of calaverite, foretelling the existence of a new gold compound previously unknown to chemists. The results of their study were published in ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.