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  Molecular Tweezers Inhibit Islet Amyloid Polypeptide Assembly and Toxicity by a New Mechanism

Lopes, D. H. J., Attar, A., Nair, G., Hayden, E. Y., Du, Z., McDaniel, K., et al. (2015). Molecular Tweezers Inhibit Islet Amyloid Polypeptide Assembly and Toxicity by a New Mechanism. ACS Chemical Biology, 10(6), 1555-1569. doi:10.1021/acschembio.5b00146.

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 Creators:
Lopes, Dahabada H. J.1, Author
Attar, Atta1, 2, Author
Nair, Gayatri1, Author
Hayden, Eric Y.1, Author
Du, Zhenming3, Author
McDaniel, Kirsten1, Author
Dutt, Som4, Author
Bandmann, Heinz4, Author
Bravo-Rodriguez, Kenny5, Author              
Mittal, Sumit5, Author              
Klärner, Frank-Gerrit4, Author
Wang , Chunyu3, Author
Sanchez-Garcia, Elsa5, Author              
Schrader, Thomas4, Author
Bitan, Gal1, 2, 6, Author
Affiliations:
1Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095-7334, United States, ou_persistent22              
2Brain Research Institute, University of California at Los Angeles, Los Angeles, California 90095-7334, United States, ou_persistent22              
3Department of Biology, Rensselaer Polytechnic Institute, Troy, New York 12180, United States, ou_persistent22              
4Institute of Organic Chemistry, University of Duisburg-Essen, 45141 Essen, Germany, ou_persistent22              
5Research Group Sánchez-García, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1950289              
6Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California 90095-7334, United States, ou_persistent22              

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 Abstract: In type-2 diabetes (T2D), islet amyloid polypeptide (IAPP) self-associates into toxic assemblies causing islet β-cell death. Therefore, preventing IAPP toxicity is a promising therapeutic strategy for T2D. The molecular tweezer CLR01 is a supramolecular tool for selective complexation of K residues in (poly)peptides. Surprisingly, it inhibits IAPP aggregation at substoichiometric concentrations even though IAPP has only one K residue at position 1, whereas efficient inhibition of IAPP toxicity requires excess CLR01. The basis for this peculiar behavior is not clear. Here, a combination of biochemical, biophysical, spectroscopic, and computational methods reveals a detailed mechanistic picture of the unique dual inhibition mechanism for CLR01. At low concentrations, CLR01 binds to K1, presumably nucleating nonamyloidogenic, yet toxic, structures, whereas excess CLR01 binds also to R11, leading to nontoxic structures. Encouragingly, the CLR01 concentrations needed for inhibition of IAPP toxicity are safe in vivo, supporting its development toward disease-modifying therapy for T2D.

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Language(s): eng - English
 Dates: 2014-05-232015-04-062015-04-062015-06-19
 Publication Status: Published in print
 Pages: 15
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1021/acschembio.5b00146
 Degree: -

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Title: ACS Chemical Biology
Source Genre: Journal
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Publ. Info: Washington, D.C. : American Chemical Society
Pages: - Volume / Issue: 10 (6) Sequence Number: - Start / End Page: 1555 - 1569 Identifier: ISSN: 1554-8929
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000035040