Macrocyclic Immunoproteasome Inhibitors as a Potential Therapy for Alzheimer's Disease

Authors

Min Jae Lee
Deepak Bhattarai
Hyeryung Jang
Ahreum Baek
In Jun Yeo
Seongsoo Lee
Zachary Miller
Sukyeong Lee
Jin Tae Hong
Dong-Eun Kim
Wooin Lee
Kyung Bo Kim

Publication Date

8-12-2021

Journal

Journal of Medicinal Chemistry

DOI

10.1021/acs.jmedchem.1c00291

PMID

34309393

PMCID

PMC10913540

PubMedCentral® Posted Date

3-5-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

no

Keywords

Alzheimer Disease, Animals, Cells, Cultured, Dose-Response Relationship, Drug, Humans, Macrocyclic Compounds, Mice, Mice, Inbred C57BL, Mice, Transgenic, Molecular Structure, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Structure-Activity Relationship, Proteasome inhibitor, Immunoproteasome, neuroinflammation, LMP2, macrocyclic peptide epoxyketone, Alzheimer’s disease

Abstract

Previously, we reported that immunoproteasome (iP)-targeting linear peptide epoxyketones improve cognitive function in mouse models of Alzheimer's disease (AD) in a manner independent of amyloid β. However, these compounds' clinical prospect for AD is limited due to potential issues, such as poor brain penetration and metabolic instability. Here, we report the development of iP-selective macrocyclic peptide epoxyketones prepared by a ring-closing metathesis reaction between two terminal alkenes attached at the P2 and P3/P4 positions of linear counterparts. We show that a lead macrocyclic compound DB-60 (

Comments

This article has been corrected. See J Med Chem. 2024 Mar 12.

Associated Data