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 iPtargeting 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 cellbased 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 (40 mg/kg) or orally (150 mg/kg) into healthy BALB/c mice, we observed considerable iP inhibition in the mouse brain, indicating good blood−brain barrier permeability and target engagement. Combined results suggest that 5 is a promising AD drug lead that may need further investigation.

Targeting Microglial Immunoproteasome: A Novel Approach in Neuroinflammatory-Related Disorders

“…Despite the recent exploration of the impact of pharmacological immunoproteasome inhibition on neurodegeneration and its promising efficacy, clinical applications of i20S inhibitors are likely to face limitations, such as poor penetration across the BBB and a short half-life. Nonetheless, significant improvements are being made to enhance the BBB permeability of these compounds, promising future therapies …”

“…This key difference led to the development of various LMP2-specific inhibitors, and most known compounds share some similar features in their structure. These compounds contain either Leu (UK-101, DB-60, DB-310 and ML604440), Cha (LU-001i) or Phe (KZR-504) moieties at the P1 position and a cyclic residue at the P3 position. , Moreover, significant efforts are underway to enhance the BBB permeability and effectiveness of i20S inhibitors, suggesting that these compounds could potentially serve as novel treatments for AD . All of these compounds also contain an epoxyketone warhead, except ML604440, which is a boronic acid derivative.…”