title: Molecular tweezers inhibit islet amyloid polypeptide assembly and toxicity by a new mechanism.
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.
authors.forename: Dahabada H J
authors.initials: DH
authors.lastname: Lopes
authors.forename: Aida
authors.initials: A
authors.lastname: Attar
authors.forename: Gayatri
authors.initials: G
authors.lastname: Nair
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Hayden
authors.affiliation: ∥Department of Biology, Rensselaer Polytechnic Institute, Troy, New York 12180, United States.
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Du
authors.forename: Kirsten
authors.initials: K
authors.lastname: McDaniel
authors.affiliation: ⊥Institute of Organic Chemistry, University of Duisburg-Essen, 45141 Essen, Germany.
authors.forename: Som
authors.initials: S
authors.lastname: Dutt
authors.affiliation: #Max-Planck-Institut für Kohlenforschung, 45470 Mülheim an der Ruhr, Germany.
authors.forename: Kenny
authors.initials: K
authors.lastname: Bravo-Rodriguez
authors.affiliation: #Max-Planck-Institut für Kohlenforschung, 45470 Mülheim an der Ruhr, Germany.
authors.forename: Sumit
authors.initials: S
authors.lastname: Mittal
authors.affiliation: ⊥Institute of Organic Chemistry, University of Duisburg-Essen, 45141 Essen, Germany.
authors.forename: Frank-Gerrit
authors.initials: FG
authors.lastname: Klärner
authors.affiliation: ∥Department of Biology, Rensselaer Polytechnic Institute, Troy, New York 12180, United States.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Wang
authors.affiliation: #Max-Planck-Institut für Kohlenforschung, 45470 Mülheim an der Ruhr, Germany.
authors.forename: Elsa
authors.initials: E
authors.lastname: Sanchez-Garcia
authors.affiliation: ⊥Institute of Organic Chemistry, University of Duisburg-Essen, 45141 Essen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schrader
authors.forename: Gal
authors.initials: G
authors.lastname: Bitan
mesh_terms: D000818:Animals; D001952:Bridged-Ring Compounds / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D058228:Islet Amyloid Polypeptide / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity; D008958:Models, Molecular; D010755:Organophosphates / Q000737:chemistry* / Q000494:pharmacology; D066329:Protein Aggregates / Q000187:drug effects; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats
chemical_list: D001952:Bridged-Ring Compounds; C583031:CLR01 compound; D007004:Hypoglycemic Agents; D058228:Islet Amyloid Polypeptide; D010755:Organophosphates; D066329:Protein Aggregates