Granzyme K (GzmK), a family of granzymes implicated in age-associated inflammatory disease, plays a key role in driving chronic inflammation by causing cell death. Despite its significant impact on diseases like asthma, psoriasis and atherosclerosis, current therapies lack focus on GzmK.

Daniel Tyrrell, Ph.D., an assistant professor in the Division of Molecular and Cellular Pathology, is leading a study aimed at addressing this issue. Tyrrell was awarded funding from Southern Research’s Station 41 Therapeutics Accelerator for his project titled, “Hit-to-Lead Optimization of a Selective Small Molecule Inhibitor of Granzyme K.” Tyrrell will collaborate with Rebecca Boohaker, Ph.D., Director of Strategic Initiatives at Southern Research, on the project. The project grant, which is milestone-based, will fund $100,000 to $200,000 in the next 1 to 2 years.

“Since GzmK is uniquely expressed in distinct subsets of T cells and differs structurally from other granzymes, it provides an opportunity for selective inhibition,” Tyrrell said.

Boohaker’s research team will identify candidate small molecule inhibitors of GzmK by in vitro screening, and Tyrrell’s research team will test these with in vivo models. As past serine protease inhibitors failed clinically, Tyrrell’s study will be the first to provide insight into new therapeutic avenues for age-associated inflammatory diseases.

“We hypothesize that selective GzmK inhibition will mitigate tissue inflammation by blocking the cytotoxic effects of T cells in autoimmune and age-related inflammatory diseases, therefore preventing inflammatory tissue damage without impairing essential immune functions,” Tyrrell said.

The researchers will utilize AI-driven virtual screening and a custom tr-FRET assay to discover and validate initial hits. These compounds will be optimized for potency and selectivity, then tested in cellular asthma and psoriasis models.