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

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

doi:10.1021/acs.jmedchem.1c00291

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

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

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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 (20) effectively inhibits the catalytic activity of iP in ABCB1-overexpressing cells (IC50: 105 nM) and has metabolic stability superior to its linear counterpart. DB-60 (20) also lowered the serum levels of IL-1α and ameliorated cognitive deficits in Tg2576 mice. The results collectively suggest that macrocyclic peptide epoxyketones have improved CNS drug properties than their linear counterparts and offer promising potential as an AD drug candidate.

Original language	English
Pages (from-to)	10934-10950
Number of pages	17
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	15
DOIs	https://doi.org/10.1021/acs.jmedchem.1c00291
State	Published - Aug 12 2021

Bibliographical note

Funding Information:
The authors thank the National Institutes of Health (R01 CA188354 to K.B.K. and R01 GM111084 to S.L.), the National Research Foundation of Korea (2017R1E1A1A01074656 to D-E.K. and MRC2017R A5A2015541 to J.T.H), and the Creative-Pioneering Researchers Program through Seoul National University (to W.L.) for financially supporting this work.

Publisher Copyright:
© 2021 American Chemical Society.

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.1c00291

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title = "Macrocyclic Immunoproteasome Inhibitors as a Potential Therapy for 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 (20) effectively inhibits the catalytic activity of iP in ABCB1-overexpressing cells (IC50: 105 nM) and has metabolic stability superior to its linear counterpart. DB-60 (20) also lowered the serum levels of IL-1α and ameliorated cognitive deficits in Tg2576 mice. The results collectively suggest that macrocyclic peptide epoxyketones have improved CNS drug properties than their linear counterparts and offer promising potential as an AD drug candidate.",

author = "Lee, {Min Jae} and Deepak Bhattarai and Hyeryung Jang and Ahreum Baek and Yeo, {In Jun} and Seongsoo Lee and Zachary Miller and Sukyeong Lee and Hong, {Jin Tae} and Kim, {Dong Eun} and Wooin Lee and Kim, {Kyung Bo}",

note = "Funding Information: The authors thank the National Institutes of Health (R01 CA188354 to K.B.K. and R01 GM111084 to S.L.), the National Research Foundation of Korea (2017R1E1A1A01074656 to D-E.K. and MRC2017R A5A2015541 to J.T.H), and the Creative-Pioneering Researchers Program through Seoul National University (to W.L.) for financially supporting this work. Publisher Copyright: {\textcopyright} 2021 American Chemical Society.",

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AU - Bhattarai, Deepak

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AU - Lee, Seongsoo

AU - Miller, Zachary

AU - Lee, Sukyeong

AU - Hong, Jin Tae

AU - Kim, Dong Eun

AU - Lee, Wooin

AU - Kim, Kyung Bo

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PY - 2021/8/12

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N2 - 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 (20) effectively inhibits the catalytic activity of iP in ABCB1-overexpressing cells (IC50: 105 nM) and has metabolic stability superior to its linear counterpart. DB-60 (20) also lowered the serum levels of IL-1α and ameliorated cognitive deficits in Tg2576 mice. The results collectively suggest that macrocyclic peptide epoxyketones have improved CNS drug properties than their linear counterparts and offer promising potential as an AD drug candidate.

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

Abstract

Bibliographical note

ASJC Scopus subject areas

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