General design of photocaged RuPHOTACs.
Image Credit: Phoebe Glazer
Scientific Frontline: Extended "At a Glance" Summary: RuPHOTACs (Ruthenium-based Photoactivated Chimeras)
The Core Concept: RuPHOTACs are light-activated molecular cages that keep protein-degrading drug molecules inactive until they are exposed to low-energy red light.
Key Distinction/Mechanism: While conventional proteolysis-targeting chimeras (PROTACs) degrade both diseased and healthy proteins systemically, RuPHOTACs utilize a ruthenium metal complex to physically block the drug from acting. Upon exposure to red light, the ruthenium cage is removed, allowing the PROTAC to selectively bind to disease-causing proteins and trigger their destruction only in the illuminated tissue.
Major Frameworks/Components:
- PROteolysis-Targeting Chimeras (PROTACs): Bifunctional catalyst molecules that simultaneously bind to a target protein and an E3 ubiquitin ligase enzyme, tagging the protein for natural cellular degradation.
- Ruthenium Photocages: A complex utilizing ruthenium, a transition metal, to block protein interactions until triggered by red light.
- Dendra2 Fusion Reporter System: A novel analytical strategy using a photoconvertible protein to accurately monitor and decouple true protein degradation rates from new protein synthesis in live, intact cells.
Branches of Science: Molecular Chemistry, Photochemistry, Pharmacology, and Cellular Biology
Future Application: The precise spatiotemporal control of RuPHOTACs paves the way for advanced, localized cancer treatments and targeted therapies that eliminate disease-driving proteins without harming surrounding healthy tissues.
Why It Matters: This technology overcomes a significant barrier in modern drug development by preventing the severe, off-target side effects often associated with systemic protein-degrading therapies, making targeted medicine safer and more viable.
Researchers have created a molecular “cage” that keeps protein-degrading drug molecules inactive until they are exposed to low-energy red light. The technology, called RuPHOTACs, controls when and where these molecules become active, which could help scientists develop treatments that destroy specific proteins while limiting unwanted effects elsewhere.
Protein-degrading technology represents a potentially transformative approach to drug therapies. PROTACs, or PROteolysis-TArgeting Chimeras, work by simultaneously binding to a protein of interest and an enzyme that “tags” that protein for degradation via the natural waste removal processes within cells. These molecules are dubbed “chimeras” because they bind to and bring together two components: the disease-associated protein and the tag-applying enzyme.
“A PROTAC is a catalyst. As soon as it is finished marking one protein for destruction, it finds another partner and binds, resulting in a much stronger sustained effect. With a PROTAC, you’re not just inhibiting the cancer-driving protein, you’re removing it,” said Edith C. (Phoebe) Glazer, professor of chemistry at North Carolina State University and corresponding author of the study.
However, the main limitation of PROTACs is their effect on surrounding tissue. Many proteins that contribute to cancer and other diseases perform important functions in healthy cells, too. A drug that destroys these proteins throughout the body could cause unwanted side effects.
“Let’s say you’re focused on cancer treatment,” Glazer said. “The problem is there are very few targets—like aberrant proteins—that are only found in cancer. Most of the time, the proteins are important for our healthy tissues too. So we need a ‘cage’; that is, a way to control when and where these PROTACs are activated.”
Glazer and her colleagues called the cage they developed a RuPHOTAC, or ruthenium-based PHOToActivated Chimera.
Ruthenium, a metal in the platinum group of the periodic table, has properties that make it useful in light-driven processes and chemical reactions. By carefully designing the ruthenium complex, the researchers created a molecular cage that responds to relatively low-energy red light, which penetrates biological tissue effectively.
“Think of the ruthenium as a beach ball that blocks the two proteins from being able to approach each other,” Glazer said. “When we remove the ruthenium by exposing it to a low-energy red light, the PROTAC can get to work.”
The researchers tested the RuPHOTAC both in vitro and in vivo in a zebrafish model. They also demonstrated a new approach to monitoring successful protein destruction by putting fluorescent tags on the target proteins of interest and measuring their numbers after uncaging the RuPHOTAC.
They found that overall, the RuPHOTAC was both nontoxic in the fish model and was effective in decreasing the numbers of targeted proteins in specific areas when exposed to low-energy red light. The researchers note, however, that the penetration of the light works best on lighter-pigmented tissues.
“This is a proof-of-concept study that we hope will lead to finer control over PROTAC technology,” Glazer said. “The ability to turn on protein degradation precisely where and when it is needed could ultimately help address one of the major challenges in developing targeted medicines for various diseases.”
Funding: The majority of its financial support from the Kentucky Cabinet for Health and Family Services under grant 1000200168. The work also received support from the National Institutes of Health under grant R01GM162746, which represents approximately 10% of the overall funding for this project.
Published in journal: Nature Communications
Authors: Dmytro Havrylyuk, Ainsley P. LaMore, Majd A. Al-Hamaly, Jessica S. Blackburn, David K. Heidary, and Edith C. Glazer
Source/Credit: North Carolina State University | Tracey Peake
Edited by: Scientific Frontline
Reference Number: chm102926_01
