New Breakthrough in Protein-Degrading Technology
Researchers at North Carolina State University have developed an innovative molecular structure known as RuPHOTACs, which activates protein-degrading drug molecules when exposed to low-energy red light. This advancement offers a method to control the activation of these molecules, potentially leading to targeted treatments that can eliminate specific proteins while minimizing adverse effects on surrounding tissues.
The technology builds on the concept of PROTACs, or PROteolysis-TArgeting Chimeras, which function by binding to a targeted protein and an enzyme that marks the protein for degradation. These chimeras work by linking two key components: the protein associated with a disease and the enzyme responsible for tagging it for breakdown.
Edith C. (Phoebe) Glazer, a chemistry professor at NC State and the study’s lead author, explained that the PROTACs act like catalysts. Once they finish marking one protein for destruction, they quickly engage with another, creating a prolonged impact. “With a PROTAC, you’re not just inhibiting the cancer-driving protein; you’re removing it,” Glazer stated.
Challenges in Current PROTAC Applications
Despite their potential, PROTACs face limitations due to their impact on healthy cells. Many proteins linked to cancer also serve essential functions in normal tissues, meaning that indiscriminate destruction could lead to unwanted side effects. Glazer emphasized the challenge of targeting aberrant proteins that are unique to cancer, as most proteins also play vital roles in healthy cells.
To overcome this, Glazer and her team engineered the RuPHOTAC, which acts as a molecular “cage.” This mechanism allows for controlled activation, ensuring that the PROTACs can be turned on only in specific locations and at particular times.
Ruthenium, a metal known for its ability to facilitate light-driven chemical reactions, is central to the design of this molecular cage. The researchers found that the RuPHOTAC responds effectively to low-energy red light, which penetrates biological tissues without damaging them.
Testing and Findings
In their experiments, the researchers evaluated the RuPHOTAC both in laboratory settings and using a zebrafish model. They introduced fluorescent markers to the target proteins, allowing them to measure the success of protein degradation following exposure to red light.
The results indicated that the RuPHOTAC was non-toxic in the zebrafish model and effectively reduced the levels of targeted proteins in designated areas when activated by low-energy red light. However, the researchers noted that the effectiveness of light penetration was greater in lighter pigmented tissues.
“This is a proof-of-concept study that we hope will lead to finer control over PROTAC technology,” Glazer remarked. The precise activation of protein degradation holds promise for addressing significant challenges in the development of targeted therapies for various diseases.
The research findings were published in Nature Communications and received financial backing primarily from the Kentucky Cabinet for Health and Family Services, with additional support from the National Institutes of Health. Other contributors from NC State included Dmytro Havrylyuk, Ainsley P. LaMore, and David K. Heidary, alongside collaborators from the University of Kentucky.
Source: NC State University
