UVA Team Aims To Design Long-Lived Peptides for More Powerful Medicines | University of Virginia School of Engineering and Applied Science

Oct 27, 2024

Peptides come and peptides go, sometimes too fast. These strings of amino acids — the building blocks of life — are of intense interest to researchers for their potential to treat everything from stroke to infection, either as the drug or the drug delivery vehicle. That is, when they last long enough to do their work.

“Peptides are potentially powerful components of medicines, because they’re just fragments of our natural proteins that our bodies can recognize,” said University of Virginia assistant professor of chemical engineering Rachel Letteri. “But one limitation is that they tend to break down quickly, so we need to figure out how to make them more stable.”

Letteri’s lab, led by her Ph.D. advisee Vincent Gray, has demonstrated an approach for overcoming the longevity problem by designing mirror images of natural peptides called coiled coils.

They described their success in Biomacromolecules.

Coiled coils, helix-shaped peptides resembling curly ribbons twisted together, are found in nearly 10% of the proteins in many organisms. They play critical roles in preparing proteins to properly carry out their jobs, in part by pulling together multiple copies of proteins.

“This happens when individual helices in a protein recognize their match and bind in a specific way, forming the coiled coil,” Letteri said. “It’s like puzzle pieces fitting together. This binding is crucial for proteins to work as they should.”

Proteins help build and repair the body, oxygenate the blood, regulate digestion and perform a host of other functions.

The binding and connecting features of coiled coils make them especially tantalizing as components for medicines, including biomaterials for tissue regeneration. Yet, like other natural peptides, they degrade quickly.

Previous research has shown that blending natural peptides with their mirror images results in excellent binding and stability. Gray and Letteri wondered if the strategy would also work with coiled coils. Could the team design mirrored coiled coils, with all their medicinal promise, to improve both their specific binding ability and longevity for medicinal use?

Gray and Letteri found that compared to natural coiled coil combinations in which the two strands spiral in same direction, their engineered coils — with the two strands spiraling in opposite directions — indeed showed stronger binding and greater longevity in biological environments.

Why does it work? Mirror-image peptides improve stability because they are not affected by enzymes that accelerate chemical breakdown of natural peptides. Moreover, the mirror images can be designed to target natural peptides and bind tightly in specific ways due to their opposite but complimentary shape — much like intertwining the fingers of your left and right hands.

While the team successfully demonstrated the concept, the research has a long way to go, Letteri said.

“Researchers are just beginning to understand how to engineer peptides to leverage specific interactions between peptides and their mirror images,” she said. “We hope that these specific, long-lasting interactions between mirror-image peptides will unlock new design tools for next-generation therapeutics and biomaterials.”

Designing Coiled Coils for Heterochiral Complexation to Enhance Binding and Enzymatic Stability was published July 9, 2024, in Biomacromolecules, a journal of the American Chemical Society.

The National Science Foundation and NIH Health Biotechnology Training Program provided funding for the research.