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

Ren, Baiping
http://rave.ohiolink.edu/etdc/view?acc_num=akron1555257099229697

Abstract Details

2019, Doctor of Philosophy, University of Akron, 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.
Jie Zheng (Committee Chair)
Pan Ernian (Committee Member)
Peng Zhenmeng (Committee Member)
Xiong Gong (Committee Member)
Zhu Jiahua (Committee Member)
167 p.
Chemical Engineering

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Citations

  • Ren, B. (2019). Molecular Design and Discovery of Single and Dual Inhibitors of Amyloid Peptides [Doctoral dissertation, University of Akron]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=akron1555257099229697

    APA Style (7th edition)

  • Ren, Baiping. Molecular Design and Discovery of Single and Dual Inhibitors of Amyloid Peptides. 2019. University of Akron, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=akron1555257099229697.

    MLA Style (8th edition)

  • Ren, Baiping. "Molecular Design and Discovery of Single and Dual Inhibitors of Amyloid Peptides." Doctoral dissertation, University of Akron, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=akron1555257099229697

    Chicago Manual of Style (17th edition)

akron1555257099229697
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© 2019, all rights reserved.
This open access ETD is published by University of Akron and OhioLINK.