What is it about?
Scientists have developed ring-shaped molecules, called macrocyclic peptides, that can tightly latch onto the Huntington’s disease protein, huntingtin (HTT). These molecules bind with high precision to specific parts of HTT, giving researchers new ways to study, and potentially control, this important protein. These molecules are like custom-designed handles: once attached, they make it much easier to grab, track, and manipulate HTT in the lab, opening up new possibilities for understanding and treating Huntington’s disease.
Featured Image
Photo by chris robert on Unsplash
Why is it important?
Huntington’s disease research has long faced a frustrating problem: the HTT protein is hard to target directly with therapeutics. HTT is a 348 kDa non-catalytic scaffold protein which means it has a large without obvious druggable pockets. This makes it difficult for traditional small molecule drugs to latch on, or to figure out where they should be targeted on this huge molecule. This study shows that macrocyclic peptides can overcome that barrier, bringing previously out-of-reach targets like HTT into play. Macrocyclic peptides are larger than traditional small molecule therapeutics and can grip flatter, more complex protein surfaces that small molecules struggle with, expanding the druggable space. These molecules bind HTT very tightly (low nanomolar affinity), each attach specifically to different regions of the protein, and are structure-validated, meaning scientists can see exactly how they interact with HTT.
Perspectives
This study gives researchers a new way to study HTT. These macrocyclic peptides are like custom-built handles that can be clipped onto specific parts of HTT. Once attached, they make it possible to pull on the protein, tracking its partners in different cell contexts and opening up a range of possibilities. Scientists could now link these handles to fluorescent tags to watch HTT in action in live cells, or to signal molecular machinery to target HTT for degradation. With further development, these peptides could be optimised into therapeutic strategies, improving their stability and delivery so they work effectively in the body. Just as importantly, having multiple peptides that bind different regions of HTT offers a toolkit for mapping exactly what each part of the protein actually does, something that has remained murky despite decades of study. Beyond Huntington’s disease, this approach could be extended to other proteins that have been considered “undruggable,” expanding the landscape of targets for drug discovery.
Prof. Rachel Harding
University of Toronto
Read the Original
This page is a summary of: High-affinity, structure-validated and selective macrocyclic peptide tools for chemical biology studies of Huntingtin, Proceedings of the National Academy of Sciences, March 2026, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2520462123.
You can read the full text:
Contributors
The following have contributed to this page
