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Chemical Chaperones Modulate the Formation of Metabolite Assemblies
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 remain elusive, an...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431448/ https://www.ncbi.nlm.nih.gov/pubmed/34502079 http://dx.doi.org/10.3390/ijms22179172 |
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author | Adsi, Hanaa Levkovich, Shon A. Haimov, Elvira Kreiser, Topaz Meli, Massimiliano Engel, Hamutal Simhaev, Luba Karidi-Heller, Shai Colombo, Giorgio Gazit, Ehud Laor Bar-Yosef, Dana |
author_facet | Adsi, Hanaa Levkovich, Shon A. Haimov, Elvira Kreiser, Topaz Meli, Massimiliano Engel, Hamutal Simhaev, Luba Karidi-Heller, Shai Colombo, Giorgio Gazit, Ehud Laor Bar-Yosef, Dana |
author_sort | Adsi, Hanaa |
collection | PubMed |
description | 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 remain 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 repertoire. 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 alteration 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 elucidate 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. |
format | Online Article Text |
id | pubmed-8431448 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-84314482021-09-11 Chemical Chaperones Modulate the Formation of Metabolite Assemblies Adsi, Hanaa Levkovich, Shon A. Haimov, Elvira Kreiser, Topaz Meli, Massimiliano Engel, Hamutal Simhaev, Luba Karidi-Heller, Shai Colombo, Giorgio Gazit, Ehud Laor Bar-Yosef, Dana Int J Mol Sci Article 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 remain 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 repertoire. 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 alteration 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 elucidate 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. MDPI 2021-08-25 /pmc/articles/PMC8431448/ /pubmed/34502079 http://dx.doi.org/10.3390/ijms22179172 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Adsi, Hanaa Levkovich, Shon A. Haimov, Elvira Kreiser, Topaz Meli, Massimiliano Engel, Hamutal Simhaev, Luba Karidi-Heller, Shai Colombo, Giorgio Gazit, Ehud Laor Bar-Yosef, Dana Chemical Chaperones Modulate the Formation of Metabolite Assemblies |
title | Chemical Chaperones Modulate the Formation of Metabolite Assemblies |
title_full | Chemical Chaperones Modulate the Formation of Metabolite Assemblies |
title_fullStr | Chemical Chaperones Modulate the Formation of Metabolite Assemblies |
title_full_unstemmed | Chemical Chaperones Modulate the Formation of Metabolite Assemblies |
title_short | Chemical Chaperones Modulate the Formation of Metabolite Assemblies |
title_sort | chemical chaperones modulate the formation of metabolite assemblies |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431448/ https://www.ncbi.nlm.nih.gov/pubmed/34502079 http://dx.doi.org/10.3390/ijms22179172 |
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