Tuning the rate of aggregation of hIAPP into amyloid using small-molecule modulators of assembly

• Published in: Nature communications Vol. 13; no. 1; pp. 1040 - 15
• Main Authors: Xu, Yong, Maya-Martinez, Roberto, Guthertz, Nicolas, Heath, George R., Manfield, Iain W., Breeze, Alexander L., Sobott, Frank, Foster, Richard, Radford, Sheena E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.02.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 101/6; 631/45; 631/57; 82/58; Agglomeration; Alzheimer's disease; Amylin; Amyloid; Amyloid - metabolism; Amyloidogenesis; Amyloidogenic Proteins - metabolism; Assembly; Binding; Chemical compounds; Chemical kinetics; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Drug development; Elongated structure; Elongation; Fibrils; Fluorescence; Humanities and Social Sciences; Humans; Islet Amyloid Polypeptide - metabolism; Islets of Langerhans - metabolism; Kinetics; Lag phase; Mass spectrometry; Mass spectroscopy; Modulators; Molecular biology; Monomers; multidisciplinary; NMR; Nuclear magnetic resonance; Nucleation; Peptides; Polypeptides; Reaction kinetics; Science; Science (multidisciplinary); Scientific imaging; Titration
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-28660-7

Human islet amyloid polypeptide (hIAPP) self-assembles into amyloid fibrils which deposit in pancreatic islets of type 2 diabetes (T2D) patients. Here, we applied chemical kinetics to study the mechanism of amyloid assembly of wild-type hIAPP and its more amyloidogenic natural variant S20G. We show that the aggregation of both peptides involves primary nucleation, secondary nucleation and elongation. We also report the discovery of two structurally distinct small-molecule modulators of hIAPP assembly, one delaying the aggregation of wt hIAPP, but not S20G; while the other enhances the rate of aggregation of both variants at substoichiometric concentrations. Investigation into the inhibition mechanism(s) using chemical kinetics, native mass spectrometry, fluorescence titration, SPR and NMR revealed that the inhibitor retards primary nucleation, secondary nucleation and elongation, by binding peptide monomers. By contrast, the accelerator predominantly interacts with species formed in the lag phase. These compounds represent useful chemical tools to study hIAPP aggregation and may serve as promising starting-points for the development of therapeutics for T2D. Here the authors carry out chemical kinetic studies revealing that aggregation of hIAPP and its variant S20G involves secondary nucleation. Two small molecules with novel scaffolds are shown to inhibit or accelerate aggregation by binding different molecular species.