Kinetic Steering of Amyloid Formation and Polymorphism by Canagliflozin, a Type-2 Diabetes Drug
Year: 2025
Type: article
Abstract: Amyloid formation is involved in widespread health conditions such as Alzheimer's disease, Parkinson's disease, and type-2 diabetes. Amyloid fibrils have a similar cross-β architecture, but fibrils formed by a single protein sequence can have diverse structures, varying with time, self-assembly conditions, and sequence modifications. Fibril structure has been proposed to be diagnostic of disease, but why different structures result under different conditions, especially in vitro, remains elusive. We previously identified a small molecule, YX-I-1, which inhibits in vitro amyloid formation by islet amyloid polypeptide (IAPP), a peptide hormone whose amyloid formation is involved in type-2 diabetes. Here, using YX-I-1 as a lead, we identified regulator-approved drugs with similar structures by chemical similarity analysis and substructure searches and monitored the effect of 24 of these potential ligands on IAPP amyloid assembly in vitro. We show that one such compound, canagliflozin (Invokana), a type-2 diabetes drug already in clinical use, can strongly delay the kinetics of IAPP amyloid formation, an activity independent of its intended mode of action [sodium-glucose linked transporter 2 (SGLT2) inhibitor] that may have important therapeutic implications. Combining analysis of amyloid self-assembly kinetics, biophysical characterization of monomer and fibril binding, and cryo-EM of the assembly products, we show that YX-I-1 and canagliflozin target IAPP early in aggregation, remodeling the energy landscape of primary nucleation and profoundly altering the resulting fibril structures. Early binding events thus imprint long-lasting effects on the amyloid structures that form.
DOI: 10.1021/jacs.4c16743
Institution: University of Leeds
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Awards: Protein-protein interactions in the early stages of amyloid assembly mechanisms, G2569377800, State of the art direct electron detection at the Astbury Biostructure Laboratory, Probing biomolecular interactions by combining ETD-tandem mass spectrometry with chemical footprinting methodologies., Modern Cryo-Electron Microscopy with Direct Electron Detection at the University of Leeds., G4686242876, The Structural Biology of Amyloid Aggregation, G804879125, Integrated computational and synthetic tools to drive the discovery of orthosteric protein-protein interaction inhibitors
OpenAlex ID: W4407857063