Molecular Design and Discovery of Single and Dual Inhibitors of Amyloid Peptides

Bibliographic Details
Main Author:	Ren, Baiping
Language:	English
Published:	University of Akron / OhioLINK 2019
Subjects:	Chemical Engineering
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=akron1555257099229697

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-akron15552570992296972021-08-03T07:10:18Z Molecular Design and Discovery of Single and Dual Inhibitors of Amyloid Peptides Ren, Baiping Chemical Engineering Amyloid aggregation and formation are the common catastrophic events pathologically linked to many neurodegenerative diseases (also namely protein-misfolded diseases, PMDs) including Alzheimer disease (AD) and type II diabetes (T2D). Specifically, Aβ and hIAPP are considered as the central pathological agents of AD and T2D, respectively. Inhibiting amyloid aggregation of Aβ and hIAPP is considering as a promising (pre)clinical strategy for preventing or delaying the onset of AD and T2D, respectively. However, neither clinical cure nor commercialized drugs is currently available for AD and T2D treatments. Current drug design strategies for new amyloid inhibitors often encounter notoriously high failure rates, mainly due to biocompatibility, safety, and blood brain barrier (BBB) permeability issues. To overcome such limits, here we propose several new design strategies, from a different angle, to discover and identify new amyloid inhibitors from FDA-approved drugs of non-neurodegenerative diseases (SIN-1 and HP-β-CD) and natural extracts from foods/herbs (Genistein and Tanshiones), for preventing the aggregation and toxicity of Aβ and/or hIAPP via different inhibition mechanisms. Among these amyloid inhibitors, biophysical experiments demonstrate that SIN-1 and HP-β-CD present a single inhibition ability to prevent Aβ oligomerization, fibrillogenesis, and toxicity associated with AD, while Genistein and Tanshiones possess a dual inhibitory activity against the aggregation and toxicity of both Aβ and hIAPP. In parallel, molecular dynamics (MD) simulations further illustrate the atomic-details of how these inhibitors bind to amyloid oligomers, interfere with β-sheet formation, and prevent their further aggregation. Taken together, the four amyloid inhibitors demonstrate different inhibition strategies against amyloid formation and toxicity.Scientific knowledge and technical protocols developed from this anti-amyloid project will hopefully bridge a gap between a fundamental understanding of amyloid structures, aggregation, toxicity and a practical structural-based design of amyloid inhibitors, both of which are critical for the development of clinical diagnostics and devices to treat neurodegenerative diseases. The obtained inhibitors and proposed approaches could also be applicable to other amyloidogenic diseases, benefiting both scientific community and entire society. 2019-07-02 English text University of Akron / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=akron1555257099229697 http://rave.ohiolink.edu/etdc/view?acc_num=akron1555257099229697 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	Chemical Engineering
spellingShingle	Chemical Engineering Ren, Baiping Molecular Design and Discovery of Single and Dual Inhibitors of Amyloid Peptides
author	Ren, Baiping
author_facet	Ren, Baiping
author_sort	Ren, Baiping
title	Molecular Design and Discovery of Single and Dual Inhibitors of Amyloid Peptides
title_short	Molecular Design and Discovery of Single and Dual Inhibitors of Amyloid Peptides
title_full	Molecular Design and Discovery of Single and Dual Inhibitors of Amyloid Peptides
title_fullStr	Molecular Design and Discovery of Single and Dual Inhibitors of Amyloid Peptides
title_full_unstemmed	Molecular Design and Discovery of Single and Dual Inhibitors of Amyloid Peptides
title_sort	molecular design and discovery of single and dual inhibitors of amyloid peptides
publisher	University of Akron / OhioLINK
publishDate	2019
url	http://rave.ohiolink.edu/etdc/view?acc_num=akron1555257099229697
work_keys_str_mv	AT renbaiping moleculardesignanddiscoveryofsingleanddualinhibitorsofamyloidpeptides
_version_	1719455114128785408

Molecular Design and Discovery of Single and Dual Inhibitors of Amyloid Peptides

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