Molecular Tweezers Inhibit Islet Amyloid Polypeptide Assembly and Toxicity by a New Mechanism
| Autor: | Chunyu Wang, Gal Bitan, Kirsten McDaniel, Aida Attar, Zhenming Du, Thomas Schrader, Dahabada H. J. Lopes, Eric Y. Hayden, Sumit Mittal, Heinz Bandmann, Som Dutt, Gayatri Nair, Frank-Gerrit Klärner, Kenny Bravo-Rodriguez, Elsa Sanchez-Garcia |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Bridged-Ring Compounds
Models Molecular endocrine system Cell Survival Supramolecular chemistry Chemie Biochemistry Protein Structure Secondary Cell Line Residue (chemistry) Protein Aggregates In vivo Insulin-Secreting Cells Animals Humans Hypoglycemic Agents Volume concentration Therapeutic strategy geography geography.geographical_feature_category Chemistry General Medicine Islet Organophosphates Islet Amyloid Polypeptide Protein Structure Tertiary Rats Toxicity Molecular Medicine Molecular tweezers Protein Binding |
| Zdroj: | Lopes, DHJ; Attar, A; Nair, G; Hayden, EY; 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. UCLA: Retrieved from: http://www.escholarship.org/uc/item/05n960rx |
| DOI: | 10.1021/acschembio.5b00146. |
| Popis: | © 2015 American Chemical Society. 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. |
| Databáze: | OpenAIRE |
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