Tauopathies such as Alzheimer’s disease are a type of neurodegenerative disorder associated with tau protein aggregation into insoluble tangles. Tau is an intrinsically disordered protein whose function is to stabilize microtubules in cells. Mutations and hyperphosphorylation of tau disrupt microtubule stabilization and promote aggregation that leads to disrupted neural processes. Progression of these diseases cause memory, behavior, and cognition problems, as well as difficulty in carrying out daily activities. One potential target to discover new treatments for tauopathies is the Hsp70 family of molecular chaperones present in eukaryotic cells. In this family are heat shock protein 70 (Hsp70/HSPA1A) and heat shock cognate 70 (Hsc70/HSPA8), which bind to misfolded proteins and are essential to proteostasis. Hsp70 and Hsc70, together with other co-chaperones, target misfolded proteins for degradation in order to limit abnormal protein accumulation inside cells. Hsp70 and Hsc70 have 85% structure homology, but Hsp70 is more effective at degrading tau whereas Hsc70 is more closely linked to associating tau with microtubules. Hsc70 also interferes with Hsp70-promoted degradation. However, Hsc70 is constitutively expressed while Hsp70 is stress-induced, which may make Hsc70 a more suitable target. Rhodacyanine derivatives have been shown to act as inhibitors of Hsp70 family protein members. These inhibitors stabilize the ADP complex that activate and increase degradation of tau. Known inhibitors have been shown to bind allosterically to a deep pocket of Hsp70/Hsc70 and not at the ATP binding site. Docking studies further show a narrowing of the binding pocket. Therefore, a primary goal of our research is to synthesize analogs to exploit this pocket and improve binding interactions. At the same time, we wish to maintain or improve the tau reducing properties of this class of compounds and improve blood-brain barrier permeability. Recent results in these areas will be presented.

Synthesis of rhodacyanine derivatives as Hsp70 inhibitors for improved tau degradation in tauopathies

2019 Spring National Meeting

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