Session: Current Topics in Biological Chemistry:

Intrinsically disorder proteins (IDPs) are a class of proteins lacking a defined tertiary structure and are known to be involved in many signaling events. However, accumulation of these aggregation-prone IDPs has shown to elicit toxic signaling events and have been implicated in the progression of a number of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Parkinson's Disease. The 20S proteasome has shown to target IDPs for degradation to maintain protein homeostasis, however, toxic accumulation of IDPs can occur due to dysregulation of the ubiquitin-proteasome system (UPS), mutations, gene amplification, or other cellular dysregulations. Furthermore, the accumulation of these aggregation-prone IDPs has shown to lead to the formation of IDP aggregates which have shown to inhibit 20S-mediated proteolysis, resulting in the additional accumulation of toxic IDP aggregates. To combat the toxic accumulation of IDPs, a new therapeutic strategy has emerged using small molecules to activate the 20S proteasome resulting in an enhanced rate of IDP degradation, thereby preventing their accumulation. Current work is underway to explore the efficacy of known 20S activators toward new IDP targets, such as the dipeptide repeat (DPR) proteins associated with ALS, as well as identify and synthetically explore novel small molecule 20S activator scaffolds to increase the chemical space of 20S activators. The antihistamine drug astemizole has recently been identified as a new 20S activator containing a novel benzimidazole scaffold, and analogues are being designed and synthesized to increase its selectivity for 20S activation over its endogenous antihistamine targets. Astemizole and a synthetic analogue have shown to be capable of enhancing 20S proteasome activity and the 20S-mediated degradation of IDPs in vitro; currently, the cellular efficacy of these compounds is being explored to further assess the potential of 20S activation as a novel therapeutic for neurodegenerative diseases.

Allison Vanecek

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