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Therapeutic Development towards Protein Misfolding Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 6391

Special Issue Editors

Department of Materials Science and Engineering, Seoul National University, Seoul 08826, Republic of Korea
Interests: amyloid; protein aggregation; protein misfolding; neurodegenerative diseases; peptide self assembly; peptide synthesis; amyloid inhibitors
Research Scientist, The Georgia Institute of Technology, Atlanta, GA, USA
Interests: chemical evolution; peptide-nucleic acid interactions; proto-peptides; peptide self-assembly; systems chemistry; biotechnology; amyloidogenesis

Special Issue Information

Dear Colleagues,

Both the self-assembly and aggregation of misfolded proteins are associated with many medical disorders, including Alzheimer’s, Parkinson’s, type-2 diabetes and certain types of cancer diseases. The onset of aggregation of the diseased proteins is not completely understood. Despite their structural and sequential differences, various diseased proteins self-assemble to form amyloid fibrils, which are intriguingly very similar in their morphology, conformation (increased content of beta structures) and properties in terms of binding specific dyes (for example, thioflavin T and Congo red). There are various factors that influence the aggregation such proteins, including sequence of the protein, post-translational modification, the presence of molecular crowding or other biomolecules (such as lipids, glycan and proteins), in addition to the pH and temperature of the environment.

Thus, it is essential to develop effective therapeutic strategies to mitigate protein aggregation and the diseases associated with this.

Dr. Ashim Paul
Dr. Moran Frenkel-Pinter
Guest Editors

Manuscript Submission Information

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Keywords

  • protein misfolding diseases
  • neurodegenerative diseases
  • protein aggregation amyloid
  • amyloid inhibitors
  • small molecules
  • post-translational modifications
  • antibody
  • drug development
  • beta-sheet breaker peptide
  • peptidomimetics
  • antibody mimetics
  • blood–brain barrier
  • molecular chaperones
  • mechanism of aggregation

Published Papers (2 papers)

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Research

21 pages, 2527 KiB  
Article
Hydration of Simple Model Peptides in Aqueous Osmolyte Solutions
by Aneta Panuszko, Maciej Pieloszczyk, Anna Kuffel, Karol Jacek, Karol A. Biernacki, Sebastian Demkowicz, Janusz Stangret and Piotr Bruździak
Int. J. Mol. Sci. 2021, 22(17), 9350; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179350 - 28 Aug 2021
Cited by 6 | Viewed by 1923
Abstract
The biology and chemistry of proteins and peptides are inextricably linked with water as the solvent. The reason for the high stability of some proteins or uncontrolled aggregation of others may be hidden in the properties of their hydration water. In this study, [...] Read more.
The biology and chemistry of proteins and peptides are inextricably linked with water as the solvent. The reason for the high stability of some proteins or uncontrolled aggregation of others may be hidden in the properties of their hydration water. In this study, we investigated the effect of stabilizing osmolyte–TMAO (trimethylamine N-oxide) and destabilizing osmolyte–urea on hydration shells of two short peptides, NAGMA (N-acetyl-glycine-methylamide) and diglycine, by means of FTIR spectroscopy and molecular dynamics simulations. We isolated the spectroscopic share of water molecules that are simultaneously under the influence of peptide and osmolyte and determined the structural and energetic properties of these water molecules. Our experimental and computational results revealed that the changes in the structure of water around peptides, caused by the presence of stabilizing or destabilizing osmolyte, are significantly different for both NAGMA and diglycine. The main factor determining the influence of osmolytes on peptides is the structural-energetic similarity of their hydration spheres. We showed that the chosen peptides can serve as models for various fragments of the protein surface: NAGMA for the protein backbone and diglycine for the protein surface with polar side chains. Full article
(This article belongs to the Special Issue Therapeutic Development towards Protein Misfolding Diseases)
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16 pages, 3132 KiB  
Article
Chemical Chaperones Modulate the Formation of Metabolite Assemblies
by Hanaa Adsi, Shon A. Levkovich, Elvira Haimov, Topaz Kreiser, Massimiliano Meli, Hamutal Engel, Luba Simhaev, Shai Karidi-Heller, Giorgio Colombo, Ehud Gazit and Dana Laor Bar-Yosef
Int. J. Mol. Sci. 2021, 22(17), 9172; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179172 - 25 Aug 2021
Cited by 7 | Viewed by 3802
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 remain elusive, and so far, no [...] Read more.
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. Full article
(This article belongs to the Special Issue Therapeutic Development towards Protein Misfolding Diseases)
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