Tuesday, December 3, 2024
12/3/2024
Project Summary With the failure of nearly all clinical trials for AD drugs in the pipeline to date, identification of a new class of drug candidates has become imperative to bring about effective AD therapies. A major obstacle is the lack of promising new drug targets unrelated to the events leading to the accumulation of the amyloid-beta (Aβ) and tau- protein. We recently reported that linear peptide epoxyketones targeting the immunoproteasome (iP), an inducible variant of the 20S constitutive proteasome (cP), may represent a new class of AD drugs that can ameliorate cognitive deficits, independently of Aβ or tau accumulation. While displaying promising efficacy, however, the prospect of these linear peptide epoxyketones for clinical use in AD appears limited at this time, due to potential issues of having a poor brain accessibility, in vivo metabolic instability, and short circulation time (largely attributable to the ABCB1-mediated drug efflux at the BBB and enzymatic hydrolysis by peptidases and epoxide hydrolases). Yet, the family of peptide epoxyketones (‘short peptides with C-terminal α′,β′-epoxyketone warhead’) remain attractive drug candidates considering their pharmacological advantages conferred by their proven target specificity for the proteasomes and long-term safety in the clinic. Our current findings reveal that some of the peptide epoxyketone family members containing a macrocycle have the ability to resist the ABCB1-mediated efflux and metabolic stability superior to their linear counterparts, and the potential to be a meaningful new treatment for patients with AD. Our objective in this application is to identify and characterize one of these macrocyclic compounds best suited for brain iP inhibition in vivo and proceed to the next phase of drug development. To do this, in aim 1 we will prepare the current sets of promising macrocyclic peptide epoxyketones with different structural features that displayed comparable target inhibition and biological activity in vitro and in cellulo on a gram scale. In aim 2, we will characterize in vivo properties of each macrocyclic peptide epoxyketone to identify a lead drug candidate. In aim 3, we will verify in vivo efficacy and the proposed mechanism of action of the lead drug candidate [iP inhibition → (NLRP3 inflammasome) → suppression of microglial IL-1α release → blockade of astrocytes transformation (to A1 subtype) → neuronal survival] using two mouse models of AD (APP/PS1 and PS19 tau transgenic mice). By completing the proposed study, we will have identified a lead candidate with the best attributes for IND enabling studies and novel mode of action. These results are expected to have an important positive impact by examining the validity of the previously untapped iP-targeting approach for AD therapy and potentially offering a new direction for AD drug discovery.
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