scholarly journals Thermodynamic and kinetic design principles for protein aggregation inhibitors

2020 ◽  
Author(s):  
Thomas C. T. Michaels ◽  
Andela Šarić ◽  
Georg Meisl ◽  
Gabriella T. Heller ◽  
Samo Curk ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Protein Misfolding ◽  
Complex Problem ◽  
Binding Rate ◽  
Potent Inhibition ◽  
Aggregation Inhibitors ◽  
Aggregation Inhibition ◽  
General Physical ◽  
Misfolding Diseases ◽  
Physical Laws

AbstractUnderstanding the mechanism of action of compounds capable of inhibiting protein aggregation is critical to the development of potential ther-apeutics against protein misfolding diseases. A fundamental challenge for progress is the range of possible target species and the disparate timescales involved, since the aggregating proteins are simultaneously the reactants, products, intermediates and catalysts of the reaction. It is a complex problem, therefore, to choose the states of the aggregating proteins that should be bound by the compounds to achieve the most potent inhibition. We present here a comprehensive kinetic theory of protein aggregation inhibition which reveals the fundamental thermodynamic and kinetic signatures characterising effective inhibitors by identifying quantitative relationships between the aggregation and binding rate constants. These results provide general physical laws to guide the design and optimisation of protein aggregation inhibitors.

scholarly journals Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors

2020 ◽  
Vol 117 (39) ◽  
pp. 24251-24257 ◽  
Author(s):  
Thomas C. T. Michaels ◽  
Andela Šarić ◽  
Georg Meisl ◽  
Gabriella T. Heller ◽  
Samo Curk ◽  
...  
Keyword(s):  
Protein Misfolding ◽  
Amyloid Fibril ◽  
Complex Problem ◽  
Fibril Formation ◽  
Amyloid Aggregation ◽  
Design And Optimization ◽  
Amyloid Fibril Formation ◽  
Potent Inhibition ◽  
General Physical ◽  
Misfolding Diseases

Understanding the mechanism of action of compounds capable of inhibiting amyloid-fibril formation is critical to the development of potential therapeutics against protein-misfolding diseases. A fundamental challenge for progress is the range of possible target species and the disparate timescales involved, since the aggregating proteins are simultaneously the reactants, products, intermediates, and catalysts of the reaction. It is a complex problem, therefore, to choose the states of the aggregating proteins that should be bound by the compounds to achieve the most potent inhibition. We present here a comprehensive kinetic theory of amyloid-aggregation inhibition that reveals the fundamental thermodynamic and kinetic signatures characterizing effective inhibitors by identifying quantitative relationships between the aggregation and binding rate constants. These results provide general physical laws to guide the design and optimization of inhibitors of amyloid-fibril formation, revealing in particular the important role of on-rates in the binding of the inhibitors.

scholarly journals Catechol-Containing Compounds are a Broad Class of Protein Aggregation Inhibitors: II. Rosmarinic Acid Potently Detoxifies Amylin Amyloid and Ameliorates Diabetic Pathology in HIP Rats

2020 ◽  
Author(s):  
Ling Wu ◽  
Paul Velander ◽  
Anne M. Brown ◽  
Yao Wang ◽  
Dongmin Liu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Protein Aggregation ◽  
Rosmarinic Acid ◽  
Protein Misfolding ◽  
Broad Class ◽  
Diabetic Patients ◽  
Aggregation Inhibitors ◽  
Misfolding Diseases

AbstractProtein aggregation is associated with a large number of human protein misfolding diseases, yet FDA-approved drugs are currently not available. Amylin amyloid and plaque depositions in the pancreas are hallmark features of type 2 diabetes. Moreover, these amyloid deposits are implicated in the pathogenesis of diabetic complications such as neurodegeneration. We recently discovered that catechols and redox-related quinones/ anthraquinones represent a broad class of protein aggregation inhibitors. Further screening of a targeted library of natural compounds in complementary medicine that were enriched with catechol-containing compounds identified rosmarinic acid as a potent inhibitor of amylin aggregation (estimated inhibitory concentration IC50 = 200-300 nM). Structure-function relationship analysis of rosmarinic acid showed the additive effects of two catechol-containing components of the RA molecule. We further showed that RA does not reverse fibrillation back to monomeric amylin, but lead to non-toxic, remodeled protein aggregates. Rosmarinic acid has significant ex vivo efficacy in reducing human amylin oligomer levels in HIP rat sera as well as in sera from diabetic patients. In vivo efficacy studies of rosmarinic acid treatment with the diabetic HIP rat model demonstrated significant reduction in amyloid islet deposition and strong mitigation of diabetic pathology. Our work provides new in vitro molecular mechanisms and in vivo efficacy insights for a model nutraceutical agent against type 2 diabetes and other aging-related protein misfolding diseases.

scholarly journals Infrared nanospectroscopy reveals the molecular interaction fingerprint of an aggregation inhibitor with single Aβ42 oligomers

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Francesco Simone Ruggeri ◽  
Johnny Habchi ◽  
Sean Chia ◽  
Robert I. Horne ◽  
Michele Vendruscolo ◽  
...  
Keyword(s):  
Small Molecules ◽  
Single Molecule ◽  
Protein Misfolding ◽  
Molecular Mechanisms ◽  
Chemical Sensitivity ◽  
Incomplete Knowledge ◽  
Parkinson’S Diseases ◽  
Aggregation Inhibitor ◽  
Misfolding Diseases

AbstractSignificant efforts have been devoted in the last twenty years to developing compounds that can interfere with the aggregation pathways of proteins related to misfolding disorders, including Alzheimer’s and Parkinson’s diseases. However, no disease-modifying drug has become available for clinical use to date for these conditions. One of the main reasons for this failure is the incomplete knowledge of the molecular mechanisms underlying the process by which small molecules interact with protein aggregates and interfere with their aggregation pathways. Here, we leverage the single molecule morphological and chemical sensitivity of infrared nanospectroscopy to provide the first direct measurement of the structure and interaction between single Aβ42 oligomeric and fibrillar species and an aggregation inhibitor, bexarotene, which is able to prevent Aβ42 aggregation in vitro and reverses its neurotoxicity in cell and animal models of Alzheimer’s disease. Our results demonstrate that the carboxyl group of this compound interacts with Aβ42 aggregates through a single hydrogen bond. These results establish infrared nanospectroscopy as a powerful tool in structure-based drug discovery for protein misfolding diseases.

Nanotechnology drives a paradigm shift on protein misfolding diseases and amyloidosis

2012 ◽  
Author(s):  
Vittorio Bellotti ◽  
Monica Stoppini
Keyword(s):  
Paradigm Shift ◽  
Protein Misfolding ◽  
Misfolding Diseases

Facile Photolithographic Fabrication of Zwitterionic Polymer Microneedles with Protein Aggregation Inhibition for Transdermal Drug Delivery

2021 ◽  
Author(s):  
Harit Pitakjakpipop ◽  
Robin Rajan ◽  
Kittipong Tantisantisom ◽  
Pakorn Opaprakasit ◽  
Duy Dang Nguyen ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Protein Aggregation ◽  
Transdermal Drug Delivery ◽  
Zwitterionic Polymer ◽  
Aggregation Inhibition

Yeast Cells as a Discovery Platform for Parkinson's Disease and other Protein Misfolding Diseases

2008 ◽  
pp. 505-536
Author(s):  
Karen L. Allendoerfer ◽  
Linhui Julie Su ◽  
Susan Lindquist
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Misfolding ◽  
Yeast Cells ◽  
Misfolding Diseases

scholarly journals SAR by kinetics for drug discovery in protein misfolding diseases

2018 ◽  
Vol 115 (41) ◽  
pp. 10245-10250 ◽  
Author(s):  
Sean Chia ◽  
Johnny Habchi ◽  
Thomas C. T. Michaels ◽  
Samuel I. A. Cohen ◽  
Sara Linse ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Protein Misfolding ◽  
Amyloid Beta Peptide ◽  
Oligomer Formation ◽  
Chemical Derivatives ◽  
Structure Activity ◽  
Beta Peptide ◽  
Misfolding Diseases ◽  
Aβ Oligomer

To develop effective therapeutic strategies for protein misfolding diseases, a promising route is to identify compounds that inhibit the formation of protein oligomers. To achieve this goal, we report a structure−activity relationship (SAR) approach based on chemical kinetics to estimate quantitatively how small molecules modify the reactive flux toward oligomers. We use this estimate to derive chemical rules in the case of the amyloid beta peptide (Aβ), which we then exploit to optimize starting compounds to curtail Aβ oligomer formation. We demonstrate this approach by converting an inactive rhodanine compound into an effective inhibitor of Aβ oligomer formation by generating chemical derivatives in a systematic manner. These results provide an initial demonstration of the potential of drug discovery strategies based on targeting directly the production of protein oligomers.

Interaction between amyloidogenic proteins and biomembranes in protein misfolding diseases: Mechanisms, contributors, and therapy

2018 ◽  
Vol 1860 (9) ◽  
pp. 1876-1888 ◽  
Author(s):  
Biao Cheng ◽  
Yang Li ◽  
Liang Ma ◽  
Zhuoyi Wang ◽  
Robert B. Petersen ◽  
...  
Keyword(s):  
Protein Misfolding ◽  
Amyloidogenic Proteins ◽  
Misfolding Diseases
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