Summary: Alzheimer’s disease has long been considered “undruggable” because the proteins involved, specifically amyloid-beta, are “disordered”—they lack a fixed shape for traditional drugs to latch onto. However, a research team has found a solution in the mirror.
By designing a synthetic “right-handed” protein fragment (a mirror image of natural proteins), they successfully intercepted and neutralized amyloid-beta. The study shows that these mirrored molecules fit together like a left and right hand, preventing the toxic proteins from clumping into brain-damaging plaques.
Key Facts
- The Shape Problem: Most drugs work like a key in a lock. Because amyloid-beta is “disordered” (constantly changing shape), it’s like a lock that keeps shifting its keyhole.
- Chirality as a Tool: In nature, amino acids are almost exclusively “left-handed.” Kobe researchers created “right-handed” versions that specifically bind to these natural proteins.
- The “Handshake” Effect: When the right-handed interceptor meets the left-handed amyloid-beta, they form a stable, locked structure. This makes it impossible for the amyloid-beta to grab other proteins and form plaques.
- 100% Cell Survival: In mouse brain cell cultures, amyloid-beta alone killed 50% of the cells. When the mirror protein was added, cell viability remained at 100%, showing the treatment’s protective power.
- Universal Potential: This “rational design” could be applied to other “undruggable” disordered proteins involved in Parkinson’s disease and certain cancers.
Source: Kobe University
Understanding how proteins interact with their own mirror images enabled a Kobe University research team to design a small mirror protein that disables a causal factor of Alzheimer’s disease, amyloid-beta.
Alzheimer’s is formed by proteins in brain cells that have lost their natural shape and have become “disordered.” The main protein involved in this is called amyloid-beta. It is thought that such disordered proteins attach to other proteins, causing them to become disordered themselves, and together, they form plaques that inhibit the function of brain cells.
Kobe University biochemical engineer MARUYAMA Tatsuo explains what makes targeting these proteins so difficult, saying: “There is a gap in how we approach proteins without a fixed structure. Many existing drug design strategies rely on well-defined structures, and we were frustrated by how limited they are when facing more flexible, complex biological targets, such as amyloid-beta.”
The key idea in how to approach this challenge came from materials science. Maruyama says, “It occurred to us that we could intercept amyloid-beta proteins by capturing them with small fragments of their mirror images and thus might be able to stop the aggregation of amyloid-beta proteins.”
Proteins, as well as their individual components called “amino acids,” can in theory occur in two forms that are mirror images to each other like the left and right hand, but in nature they are predominantly composed of only one form.
It has been known that short chains of “left-handed” and artificially created “right-handed” amino acids can interact and form stable structures, but a rational design exploiting this mechanism has been absent.
In the scientific journal Chemistry — A European Journal, Maruyama and his team now present a systematic study of small model proteins to find out which molecular mechanisms are important for “left-handed” and “right-handed” proteins to bind to each other efficiently.
The Kobe University group then used this new-found understanding to design a short “right-handed” amino acid chain that can efficiently bind to the Alzheimer’s-causing amyloid-beta protein and under the tested conditions inhibited the protein better than a different currently promising drug candidate molecule. The interaction can be likened to a right and a left hand fitting together, making it impossible for the left arm to grab other things.
“To me, the most exciting aspect of this study is that the simple and intuitive principle of mirrored molecules — a phenomenon chemists call ‘chirality’ — can be used as a design tool for molecular recognition. It connects a fundamental concept in chemistry with a very challenging problem in biology,” says Maruyama.
The group further performed tests with mouse brain cell cultures to find out how effective their protein would be under more biological conditions. First, they made sure that their “right-handed” interceptor protein did not negatively affect viability of brain cells by itself.
Then, they showed that while the viability of the cells dropped to only 50% when exposed to amyloid-beta, cells that also got the interceptor protein did not show any reduced viability, proving that their approach seems to work.
Disordered proteins are also implicated in other diseases such as Parkinson’s and some cancers. “Because of their unstable nature, such proteins have been considered ‘undruggable,’” says Maruyama explaining the wider implications of his team’s findings.
They thus hope that their approach speeds up drug development from trial and error to a more systematic, rational design of a new class of therapeutic molecules. Maruyama closes, saying, “This result feels like a starting point rather than an endpoint.”
Funding: This research was funded by the Nakatani Foundation for Advancement of Measuring Technologies in Biomedical Engineering (grant 2022S230), Toyota Physical and Chemical Research, Noritz Nukumori Foundation (grant RS2408), Koyanagi Zaidan, the Canon Foundation, the Suzuken Memorial Foundation, the Japan Agency for Medical Research and Development (grants 24ek0109691, 24ym0126808j0003) and the Japan Society for the Promotion of Science (grants 23H01774, 23K13610). It was conducted in collaboration with researchers from Kindai University.
Key Questions Answered:
A: Natural proteins are “left-handed.” If you send in another left-handed protein, they often just slide past each other or clump together. But a “right-handed” protein creates a perfect, stable “handshake” with the target. It’s a chemical trick that allows scientists to grab onto slippery, shape-shifting proteins that normal drugs can’t catch.
A: The study focused on inhibition—stopping the proteins from forming those toxic clumps in the first place. By “capturing” the fragments early, the mirror protein prevents the chain reaction that leads to brain cell death.
A: While still in the early stages, the researchers found that the mirror protein did not harm healthy brain cells at all. Because these right-handed proteins are synthetic and “invisible” to many natural enzymes that break down left-handed proteins, they might actually stay in the body longer and be more effective than traditional drug candidates.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Alzheimer’s disease research news
Author: Daniel Schenz
Source: Kobe University
Contact: Daniel Schenz – Kobe University
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“A Chirality-Guided Molecular Recognition Strategy for Targeting Intrinsically Disordered Proteins” by Kenta Morita, Shiho Seguchi, Ayaka Hayashi, Haruhiko Miwa, Satoru Uchida, Kunihisa Sugimoto, Eri Chatani, Atsuo Tamura, Tatsuo Maruyama. Chemistry – A European Journal
DOI:10.1002/chem.70889
Abstract
A Chirality-Guided Molecular Recognition Strategy for Targeting Intrinsically Disordered Proteins
Some peptide sequences are known to interact with their enantiomers to form stereocomplexes. However, the sequence-dependent conditions required for stereocomplexation have not been thoroughly elucidated.
Here, we present a systematic investigation of peptide stereocomplexation using short tripeptides and their enantiomers.
Stereocomplexation was evaluated by aggregate formation in mixed aqueous solutions, and single-crystal X-ray diffraction revealed racemic crystals. Stereocomplexation was driven by hydrophobic interactions between phenylalanine residues and electrostatic interactions involving lysine and the C-terminus.
Thermodynamic and structural features of the complexation were further elucidated by calorimetry, simulations, and fluorescence assays. On the basis of these insights, a D-peptide (Ac-fffakr5-NH2) was rationally designed to target the –FFAE– motif of amyloid β42 (Aβ42), a pathological intrinsically disordered protein.
This D-peptide inhibited the fibrillization and cytotoxicity of Aβ42 in neuronal-like cells, outperforming a clinical candidate, peptide drug RD2.
These findings establish peptide stereocomplexation as a viable strategy for constructing sequence-targeting ligands even against intrinsically disordered proteins.
