Research

Activation and Inhibition of Proteasomes Through Small Molecules and Bioimaging :

Small-Molecule Proteasome Activators: A New Frontier in Neurotherapeutics

Protein homeostasis (proteostasis) plays a vital role in maintaining the stability, integrity, and functionality of the cellular proteome. This delicate balance is regulated by an intricate network of systems, including translational machinery, molecular chaperones, the ubiquitin-proteasome system (UPS), and the autophagy-lysosome pathway. Emerging evidence indicates that impairments in protein degradation pathways—particularly the UPS and autophagy—lead to the accumulation of misfolded or aggregated proteins in neurons, a hallmark of several neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s disease. Compounding this issue, aging is known to reduce UPS efficiency, thereby increasing susceptibility to these disorders. Despite the profound impact of neurodegenerative diseases on millions globally, current treatment options remain largely symptomatic, with no available therapeutics that effectively halt or reverse disease progression. This underscores the urgent need for novel therapeutic strategies.

In our lab, we are actively engaged in designing and developing small-molecule proteasome activators to enhance proteasomal activity. Our approach focuses on targeting intrinsically disordered proteins (IDPs)—a class of aggregation-prone proteins commonly associated with neurological disorders. By stimulating proteasome-mediated degradation of these proteins, we aim to restore cellular proteostasis and offer a promising therapeutic avenue for combating neurodegenerative and other proteotoxic diseases.

Proteasome Inhibitor:

The Proteasome degrades damaged, oxidized, or misfolded proteins and plays a vital role in regulating proteins that control the cell cycle, transcription factors, and cell growth. Therefore, the continued health of the malignant cells, as opposed to normal cells, may depend on the degradation of damaged proteins. So, proteasome inhibition is a targeted therapy for cancer to promote cell cycle arrest or apoptosis. Bortezomib is the first selective, reversible, and only proteasome inhibitor for treating multiple myeloma. But bortezomib displays severe side effects due to non-specific cytotoxicity towards healthy tissue. So, there is a clear need to develop new proteasome inhibitors with improved safety and efficacy profiles.  In our lab, we have developed a series of novel boronopeptide proteasome inhibitors with selective anticancer activity. These compounds show potent 20S proteasome inhibition and strong selectivity toward MCF7 breast cancer cells. We explored their in-depth mode of action using 3D spheroids and mechanistic assays, including proteomics, ROS generation, cell cycle, mitochondrial dysfunction, and apoptosis. Our findings highlight the potential of boron-based inhibitors as targeted therapeutics in breast cancer. We developed a tripeptide vinyl sulfone based on azobenzene for proteasome inhibition studies. These proteasome inhibitors exhibit photo-switchable activity upon exposure to 365 nm light irradiation. This photo peptide exhibits photo-responsive inhibition property.

Key publications: S. Pradhan, S. Sarker, and P. Thilagar* J. Med. Chem. 2024