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Enantioselective degrader for elimination of extracellular aggregation-prone proteins hIAPP associated with Type 2 Diabetes
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Liu, Zhenqi, Yu, Dongqin, Song, Hualong, Postings, Miles L., Scott, Peter, Wang, Zhao, Ren, Jinsong and Qu, Xiaogang (2023) Enantioselective degrader for elimination of extracellular aggregation-prone proteins hIAPP associated with Type 2 Diabetes. ACS Nano, 17 (9). pp. 8141-8152. doi:10.1021/acsnano.2c11476 ISSN 1936-086X.
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WRAP-Enantioselective degrader-elimination-extracellular-aggregation-prone-type-2-diabetes-23.pdf - Accepted Version - Requires a PDF viewer. Download (2249Kb) | Preview |
Official URL: https://doi.org/10.1021/acsnano.2c11476
Abstract
Targeted protein degradation has demonstrated the power to modulate protein homeostasis. For overcoming the limitation to intracellular protein degradation, lysosome targeting chimeras have been recently developed and successfully utilized to degrade a range of disease-relevant extracellular and membrane proteins. Inspired by this strategy, here we describe our proof-of-concept studies using metallohelix-based degraders to deliver the extracellular human islet amyloid polypeptide (hIAPP) into the lysosomes for degradation. Our designed metallohelix can bind and inhibit hIAPP aggregation, and the conjugated tri-GalNAc motif can target macrophage galactose-type lectin 1 (MGL1), yielding chimeric molecules that can both inhibit hIAPP aggregation and direct the bound hIAPP for lysosomal degradation in macrophages. Further studies demonstrate that the enhanced hIAPP clearance has been through the endolysosomal system and depends on MGL1-mediated endocytosis. Intriguingly, Λ enantiomers show even better efficiency in preventing hIAPP aggregation and promoting internalization and degradation of hIAPP than Δ enantiomers. Moreover, metallohelix-based degraders also faciltate the clearance of hIAPP through asialoglycoprotein receptor in liver cells. Overall, our studies demonstrate that chiral metallohelix can be employed for targeted degradation of extracellular misfolded proteins and possess enantioselectivity.
Item Type: | Journal Article | ||||||||||||||||||
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Subjects: | Q Science > QD Chemistry Q Science > QH Natural history Q Science > QP Physiology Q Science > QR Microbiology |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||||||||||||
SWORD Depositor: | Library Publications Router | ||||||||||||||||||
Library of Congress Subject Headings (LCSH): | Proteolysis, Decomposition (Chemistry), Proteins -- Synthesis , Homeostasis, Lysosomes , Amyloid | ||||||||||||||||||
Journal or Publication Title: | ACS Nano | ||||||||||||||||||
Publisher: | American Chemical Society (ACS) | ||||||||||||||||||
ISSN: | 1936-086X | ||||||||||||||||||
Official Date: | 9 May 2023 | ||||||||||||||||||
Dates: |
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Volume: | 17 | ||||||||||||||||||
Number: | 9 | ||||||||||||||||||
Page Range: | pp. 8141-8152 | ||||||||||||||||||
DOI: | 10.1021/acsnano.2c11476 | ||||||||||||||||||
Status: | Peer Reviewed | ||||||||||||||||||
Publication Status: | Published | ||||||||||||||||||
Re-use Statement: | This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Nano, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acsnano.2c11476 | ||||||||||||||||||
Access rights to Published version: | Restricted or Subscription Access | ||||||||||||||||||
Copyright Holders: | Copyright © 2023 American Chemical Society | ||||||||||||||||||
Date of first compliant deposit: | 2 May 2023 | ||||||||||||||||||
Date of first compliant Open Access: | 14 April 2024 | ||||||||||||||||||
RIOXX Funder/Project Grant: |
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