Brain-Permeable Immunoproteasome-Targeting Macrocyclic Peptide Epoxyketones for Alzheimer's Disease.

ABSTRACT: Previously, we demonstrated that linear peptide epoxyketones targeting the immunoproteasome (iP) could ameliorate cognitive deficits in mouse models of Alzheimer's disease (AD) independently of amyloid deposition. We also reported the first iP-targeting macrocyclic peptide epoxyketones, which exhibit improved metabolic stability compared with their linear counterparts. Here, we prepared additional macrocyclic peptide epoxyketones and compared them with existing macrocyclic iP inhibitors by assessing Caco2 cell-based permeability and microsomal stability, providing the four best macrocyclic iP inhibitors. We then evaluated the four compounds using the Ames test and the potency assays in BV2 cells, selecting compound 5 as our AD drug lead. When 5 was administered intravenously

SUBMITTER: Park JE 

PROVIDER: S-EPMC11733980 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature