Chemical chaperones modulate the formation of metabolite assemblies

Hanaa Adsi, Shon A. Levkovich, Elvira Haimov, Topaz Kreiser, Massimiliano Meli, Hamutal Engel, Luba Simhaev, Shai Karidi-Heller, Giorgio Colombo, Ehud Gazit, Dana Laor Bar-Yosef

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

The formation of amyloid-like structures by metabolites is associated with several inborn errors of metabolism (IEMs). These structures display most of the biological, chemical and physical properties of protein amyloids. However, the molecular interactions underlying the assembly re-main elusive, and so far, no modulating therapeutic agents are available for clinical use. Chemical chaperones are known to inhibit protein and peptide amyloid formation and stabilize misfolded enzymes. Here, we provide an in-depth characterization of the inhibitory effect of osmolytes and hydrophobic chemical chaperones on metabolite assemblies, thus extending their functional reper-toire. We applied a combined in vivo-in vitro-in silico approach and show their ability to inhibit metabolite amyloid-induced toxicity and reduce cellular amyloid content in yeast. We further used various biophysical techniques demonstrating direct inhibition of adenine self-assembly and alter-ation of fibril morphology by chemical chaperones. Using a scaffold-based approach, we analyzed the physiochemical properties of various dimethyl sulfoxide derivatives and their role in inhibiting metabolite self-assembly. Lastly, we employed whole-atom molecular dynamics simulations to elu-cidate the role of hydrogen bonds in osmolyte inhibition. Our results imply a dual mode of action of chemical chaperones as IEMs therapeutics, that could be implemented in the rational design of novel lead-like molecules.

Original languageEnglish
Article number9172
JournalInternational Journal of Molecular Sciences
Volume22
Issue number17
DOIs
StatePublished - 25 Aug 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Funding

Funding: This research was funded by the Israel Science Foundation, grant number 1558/19 (E.G.). H.A. received support from the Ariane de Rothschild Women Doctoral Program. The APC was funded by the Israel Science Foundation, grant number 1558/19. Acknowledgments: We thank A. Lichtenstein for confocal microscopy analysis, O. Sagi‐Assif for the flow cytometry, and A. Abashidze for assistance with the generation of the heat maps. We thank the members of the Gazit laboratory and the members of the BLAVATNIK CENTER for Drug Dis‐ covery, funded by Len Blavatnik and the Blavatnik Family Foundation, for helpful discussions.

FundersFunder number
Ariane de Rothschild Women Doctoral Program
Blavatnik Family Foundation
Israel Science Foundation1558/19

    Keywords

    • Adenine
    • Amyloid formation
    • Chemical chaperones
    • Hydrophobic compounds
    • Inborn errors of metabolism
    • Metabolite assemblies
    • Osmolytes

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