In a study published in the Journal of Medicinal Chemistry, “Immunoproteasome as a Target for Prodrugs,” a UC Irvine School of Pharmacy & Pharmaceutical Sciences-led research team analyzed the potential of a protein degradation mechanism as a resolution to a long-standing issue in the world of medicine — how to treat disease without damaging nearby healthy cells.
“One of the biggest challenges in drug discovery remains the ability to target a diseased cell population while leaving the healthy tissue unaffected. Especially in diseases such as cancer, the off-target effects of many current chemotherapies can lead to harmful side effects, and minimizing the chances of that would greatly improve our ability to treat these diseases,” said UC Irvine School of Pharmacy & Pharmaceutical Sciences associate professor Dr. Darci J. Trader, who authored the study along with Trader Lab researcher and PhD in Pharmacological Sciences student Cody A. Loy and a Purdue University researcher.
To address this problem, the research team looked to the immunoproteasome.
“For our cells to maintain homeostasis, they are constantly undergoing a cycle of protein synthesis and protein degradation to eliminate the unwanted or damaged proteins. The machinery that is responsible for this degradation is known as the proteasome,” Dr. Trader explained. “There is an additional isoform that is often upregulated in a variety of disease states — such as inflammatory disease, autoimmune disorders, and cancer — known as the immunoproteasome. The immunoproteasome can degrade the same proteins as the standard proteasome; however, due to differences in its structure, it generates products that differ from the standard proteasome and are beneficial to our immune response.”
In the immunoproteasome, the researchers saw a possible solution to the negative effects of chemotherapy and other treatments that can damage healthy cells in the process of eliminating disease. They incorporated various therapies, including doxorubicin (a chemotherapy agent) and ARV-771 (a targeted protein degrader), which, when activated via interaction with the immunoproteasome, effectively targeted cancerous cells without impacting healthy cells.
“We utilized a recognition sequence we had previously identified that is specific for the immunoproteasome and appended different therapies that would be ineffective in healthy cells, but once liberated by the immunoproteasome in disease cells, would be able to elicit their mechanism of action,” said Dr. Trader. “Utilizing the immunoproteasome as a prodrug uncaging enzyme allowed us to eliminate the off-target effects of doxorubicin, a chemotherapy that is currently in the clinic.”
This research is an initial step in the team’s efforts to use the immunoproteasome in the discovery and development of therapies that can effectively treat cancer and other diseases with minimal damage to healthy cells and resulting side effects.
“As this was the first proof-of-concept that the immunoproteasome could be harnessed in this fashion therapeutically, we are currently undergoing follow-up studies on what agents would be most effective to release from our peptide to elicit the greatest therapeutic effect in cancerous cells, while leaving the healthy tissue alone,” Dr. Trader stated. “We also believe this technology has potential to be used beyond chemotherapy, as the immunoproteasome can be expressed in a variety of disease states, giving us an opportunity to improve the selectivity of a variety of medicines for a variety of targets using one enzyme complex.”
