Targeting Quadruplex Binding in ALS
Abstract
A major ongoing problem with the development of drugs for ALS is that there are many different proteins that can originate the disease. Standard drug-design efforts attempt to design a specific compound that inhibits a specific protein that will halt the disease. In ALS, while this strategy could work for some patients, it will likely fail for others that have different proteins at fault. Therefore, we are focusing on common properties of the proteins involved in ALS. Designing drugs in this fashion makes it more likely that we can develop drugs that will be effective for a wide swath of ALS patients. The particular property we are focusing on is the ability to bind G-quadruplex nucleic acid structures. G-quadruplexes are a specific shape of nucleic acid that we have recently found to be important in protein oligomerization, like that seen in ALS. Furthermore, a large number of proteins implicated in ALS have recently been found to bind G-quadruplexes. Our goal is to leverage this knowledge into designing G-quadruplex mimic molecules that can replace the natural G-quadruplex binding of ALS disease-related proteins and thereby reduce their propensity to aggregate. The timeline of this proposal is to use this two-year period to design inhibitors and test them in cell and tissue model systems for ALS. If successful, the next step would be testing these compounds in animal models and prepping them for human deliverability. Overall, the goal is to both design successful drugs for ALS and to introduce a new paradigm for drug design in diseases like ALS with multiple potential origins.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210218
Entities
People
- Scott Horowitz
Organizations
- United States Army
- University of Denver