Chemistry

Designing long-lived peptides for more potent drugs

Diagram of helical wheel. (A) K47; (B) K311. Helical wheel generated using HeliQuest (https://heliquest.ipmc.cnrs.fr/). (C) Sequences of K47 and K311 aligned with heptad abcdefg and hendecad abcdefghijk registers. Credit: Biomacromolecules (2024). DOI: 10.1021/acs.biomac.4c00661

Peptides may appear and disappear too quickly. These series of amino acids, the building blocks of life, are of intense interest to researchers because of their potential to treat everything from stroke to infections as drugs or drug delivery vehicles. That is, when it lasts long enough to do the job.

“Peptides have the potential to be powerful ingredients in medicines because they are just fragments of natural proteins that our bodies can recognize,” said Rachel Letteri, assistant professor of chemical engineering at the University of Virginia. “But one limitation is that they tend to break quickly, so we need to find ways to make them more stable.”

Letteri’s lab is led by her Ph.D. Advisor Vincent Gray demonstrated an approach to overcome the longevity problem by designing mirror images of natural peptides called coiled coils.

They described their successes in the field of biopolymers.

Coiled coil plays an important role

Coiled coils are helical peptides that resemble curly ribbons and are found in nearly 10% of proteins in many living organisms. They play an important role in preparing proteins to properly perform their jobs, such as holding multiple copies of a protein together.

“This happens when the individual helices of the protein recognize a match and join together in a specific way, forming a coiled coil,” Letteri said. “It’s like the pieces of a puzzle fitting together. This bond is important for the protein to function properly.”

Protein helps build and repair the body, oxygenates the blood, regulates digestion, and performs many other functions.

The bonding and connectivity characteristics of coiled coils make them particularly attractive as components of pharmaceuticals, including biomaterials for tissue regeneration. However, like other natural peptides, they degrade quickly.

Coiled coil mirror extends peptide lifetime

Previous studies have shown that blending a natural peptide with its mirror image provides superior binding and stability. Gray and Letteri wondered if this strategy might also work with coiled coils. Could the research team design a mirrored coiled coil with all the medicinal properties to improve both specific binding capacity and medicinal longevity?

Gray and Letteri found that compared to a natural coiled-coil combination in which the two strands spiral in the same direction, artificial coils in which the two strands spiral in opposite directions are actually stronger in biological environments. It was found that it exhibits better bonding and longer lifetime.

Why is it effective? Mirror-image peptides are more stable because they are not affected by enzymes that promote chemical degradation of natural peptides. Additionally, mirror images can be designed to target natural peptides and bind tightly in specific ways, similar to how the fingers of the left and right hands intertwine, as they are opposite but complementary shapes.

Letteri said the team was successful in proving the concept, but the research still has a long way to go.

“Researchers are just beginning to understand how to manipulate peptides to take advantage of specific interactions between a peptide and its mirror image,” she said. “We hope that these specific and long-lasting interactions between mirror peptides will unlock new design tools for the next generation of therapeutics and biomaterials.”

Further information: Vincent P. Gray et al, Design of coiled coils for heterochiral complexes to enhance binding and enzyme stability, Biopolymers (2024). DOI: 10.1021/acs.biomac.4c00661

Provided by University of Virginia

Citation: Designing Long-Lived Peptides for More Potent Medicines (October 28, 2024), October 28, 2024 at https://phys.org/news/2024-10-peptides-powerful-medicines. Retrieved from html

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