scholarly journals Infrared Nanospectroscopy Reveals the Molecular Interaction Fingerprint of an Aggregation Inhibitor with Single Aβ42 Oligomers

2020 ◽  
Author(s):  
Francesco Simone Ruggeri ◽  
Johnny Habchi ◽  
Sean Chia ◽  
Michele Vendruscolo ◽  
Tuomas P. J. Knowles
Keyword(s):  
Small Molecules ◽  
Single Molecule ◽  
Protein Misfolding ◽  
Molecular Mechanisms ◽  
Chemical Sensitivity ◽  
Single Molecule Level ◽  
Incomplete Knowledge ◽  
Parkinson’S Diseases ◽  
Aggregation Inhibitor ◽  
Misfolding Diseases

ABSTRACTVery significant 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 level morphological and chemical sensitivity of infrared nanospectroscopy to provide the first direct measurement of the interaction between single Aβ42 oligomeric and fibrillar species and an aggregation inhibitor, bexarotene, originally an anticancer drug capable recently shown to be able to inhibit Aβ42 aggregation in animal models of Alzheimer’s disease. Our results demonstrate that the carbonyl group of this compound interacts with Aβ42 aggregates through a single hydrogen bond. These results establish infrared nanospectroscopy as powerful tool in structure-based drug discovery for 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.

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.

scholarly journals Biophysical studies of protein misfolding and aggregation in in vivo models of Alzheimer's and Parkinson's diseases

2020 ◽  
Vol 53 ◽  
Author(s):  
Tessa Sinnige ◽  
Karen Stroobants ◽  
Christopher M. Dobson ◽  
Michele Vendruscolo
Keyword(s):  
Protein Misfolding ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Therapeutic Interventions ◽  
In Vivo Models ◽  
Disease Modifying Drugs ◽  
Parkinson’S Diseases ◽  
Protein Misfolding And Aggregation

Abstract Neurodegenerative disorders, including Alzheimer's (AD) and Parkinson's diseases (PD), are characterised by the formation of aberrant assemblies of misfolded proteins. The discovery of disease-modifying drugs for these disorders is challenging, in part because we still have a limited understanding of their molecular origins. In this review, we discuss how biophysical approaches can help explain the formation of the aberrant conformational states of proteins whose neurotoxic effects underlie these diseases. We discuss in particular models based on the transgenic expression of amyloid-β (Aβ) and tau in AD, and α-synuclein in PD. Because biophysical methods have enabled an accurate quantification and a detailed understanding of the molecular mechanisms underlying protein misfolding and aggregation in vitro, we expect that the further development of these methods to probe directly the corresponding mechanisms in vivo will open effective routes for diagnostic and therapeutic interventions.

scholarly journals Catechins as Tools to Understand the Molecular Basis of Neurodegeneration

Molecules ◽  
2020 ◽  
Vol 25 (16) ◽  
pp. 3571
Author(s):  
Karla Martinez Pomier ◽  
Rashik Ahmed ◽  
Giuseppe Melacini
Keyword(s):  
Phenolic Compounds ◽  
Neurodegenerative Disorders ◽  
Molecular Basis ◽  
Protein Misfolding ◽  
Molecular Mechanisms ◽  
Amyloid Aggregation ◽  
Amyloid Aggregates ◽  
Parkinson’S Diseases ◽  
Pharmacokinetic Properties ◽  
Self Association

Protein misfolding as well as the subsequent self-association and deposition of amyloid aggregates is implicated in the progression of several neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases. Modulators of amyloidogenic aggregation serve as essential tools to dissect the underlying molecular mechanisms and may offer insight on potential therapeutic solutions. These modulators include green tea catechins, which are potent inhibitors of amyloid aggregation. Although catechins often exhibit poor pharmacokinetic properties and bioavailability, they are still essential tools for identifying the drivers of amyloid aggregation and for developing other aggregation modulators through structural mimicry. As an illustration of such strategies, here we review how catechins have been used to map the toxic surfaces of oligomeric amyloid-like species and develop catechin-based phenolic compounds with enhanced anti-amyloid activity.

scholarly journals How Microbes Use Force To Control Adhesion

2020 ◽  
Vol 202 (12) ◽  
Author(s):  
Albertus Viljoen ◽  
Johann Mignolet ◽  
Felipe Viela ◽  
Marion Mathelié-Guinlet ◽  
Yves F. Dufrêne
Keyword(s):  
Single Molecule ◽  
Molecular Mechanisms ◽  
Flow Chamber ◽  
Microbial Adhesion ◽  
Single Molecule Level ◽  
Force Microscopy ◽  
Atomic Force ◽  
Adhesive Interactions ◽  
And Function ◽  
Mechanisms Of Adhesion

ABSTRACT Microbial adhesion and biofilm formation are usually studied using molecular and cellular biology assays, optical and electron microscopy, or laminar flow chamber experiments. Today, atomic force microscopy (AFM) represents a valuable addition to these approaches, enabling the measurement of forces involved in microbial adhesion at the single-molecule level. In this minireview, we discuss recent discoveries made applying state-of-the-art AFM techniques to microbial specimens in order to understand the strength and dynamics of adhesive interactions. These studies shed new light on the molecular mechanisms of adhesion and demonstrate an intimate relationship between force and function in microbial adhesins.

scholarly journals Dark noise and retinal degeneration from D190N-rhodopsin

2020 ◽  
Vol 117 (37) ◽  
pp. 23033-23043 ◽  
Author(s):  
Daniel Silverman ◽  
Zuying Chai ◽  
Wendy W. S. Yue ◽  
Sravani Keerthi Ramisetty ◽  
Sowmya Bekshe Lokappa ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Single Molecule ◽  
Protein Misfolding ◽  
Outer Segment ◽  
Segment Length ◽  
Single Molecule Level ◽  
Dark Noise ◽  
Order Of Magnitude ◽  
Human Mutation ◽  
Unclear Etiology

Numerous rhodopsin mutations have been implicated in night blindness and retinal degeneration, often with unclear etiology. D190N-rhodopsin (D190N-Rho) is a well-known inherited human mutation causing retinitis pigmentosa. Both higher-than-normal spontaneous-isomerization activity and misfolding/mistargeting of the mutant protein have been proposed as causes of the disease, but neither explanation has been thoroughly examined. We replaced wild-type rhodopsin (WT-Rho) in RhoD190N/WT mouse rods with a largely “functionally silenced” rhodopsin mutant to isolate electrical responses triggered by D190N-Rho activity, and found that D190N-Rho at the single-molecule level indeed isomerizes more frequently than WT-Rho by over an order of magnitude. Importantly, however, this higher molecular dark activity does not translate into an overall higher cellular dark noise, owing to diminished D190N-Rho content in the rod outer segment. Separately, we found that much of the degeneration and shortened outer-segment length of RhoD190N/WT mouse rods was not averted by ablating rod transducin in phototransduction—also consistent with D190N-Rho’s higher isomerization activity not being the primary cause of disease. Instead, the low pigment content, shortened outer-segment length, and a moderate unfolded protein response implicate protein misfolding as the major pathogenic problem. Finally, D190N-Rho also provided some insight into the mechanism of spontaneous pigment excitation.

scholarly journals Modulating protein quality control

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lars Plate ◽  
Ryan J Paxman ◽  
R Luke Wiseman ◽  
Jeffery W Kelly
Keyword(s):  
Quality Control ◽  
Small Molecules ◽  
Unfolded Protein Response ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Misfolding Diseases ◽  
Protein Response

Small molecules that modulate the unfolded protein response have the potential to treat a variety of human protein misfolding diseases.

scholarly journals Visualizing mutagenic repair: novel insights into bacterial translesion synthesis

2020 ◽  
Vol 44 (5) ◽  
pp. 572-582 ◽  
Author(s):  
Asha Mary Joseph ◽  
Anjana Badrinarayanan
Keyword(s):  
Single Molecule ◽  
Molecular Mechanisms ◽  
Translesion Synthesis ◽  
Dna Lesions ◽  
Current Status ◽  
Genome Maintenance ◽  
Single Molecule Level ◽  
Repair Mechanisms ◽  
Domains Of Life ◽  
Induced Mutagenesis

ABSTRACT DNA repair is essential for cell survival. In all domains of life, error-prone and error-free repair pathways ensure maintenance of genome integrity under stress. Mutagenic, low-fidelity repair mechanisms help avoid potential lethality associated with unrepaired damage, thus making them important for genome maintenance and, in some cases, the preferred mode of repair. However, cells carefully regulate pathway choice to restrict activity of these pathways to only certain conditions. One such repair mechanism is translesion synthesis (TLS), where a low-fidelity DNA polymerase is employed to synthesize across a lesion. In bacteria, TLS is a potent source of stress-induced mutagenesis, with potential implications in cellular adaptation as well as antibiotic resistance. Extensive genetic and biochemical studies, predominantly in Escherichia coli, have established a central role for TLS in bypassing bulky DNA lesions associated with ongoing replication, either at or behind the replication fork. More recently, imaging-based approaches have been applied to understand the molecular mechanisms of TLS and how its function is regulated. Together, these studies have highlighted replication-independent roles for TLS as well. In this review, we discuss the current status of research on bacterial TLS, with emphasis on recent insights gained mostly through microscopy at the single-cell and single-molecule level.

scholarly journals Membrane Interactions and Toxicity by Misfolded Protein Oligomers

2021 ◽  
Vol 9 ◽  
Author(s):  
Mario Gonzalez-Garcia ◽  
Giuliana Fusco ◽  
Alfonso De Simone
Keyword(s):  
Protein Misfolding ◽  
Direct Interaction ◽  
Misfolded Protein ◽  
Therapeutic Approaches ◽  
Cellular Toxicity ◽  
Amyloid Aggregates ◽  
Parkinson’S Diseases ◽  
Transient Interactions ◽  
Misfolding Diseases

The conversion of otherwise soluble proteins into insoluble amyloid aggregates is associated with a range of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases, as well as non-neuropathic conditions such as type II diabetes and systemic amyloidoses. It is increasingly evident that the most pernicious species among those forming during protein aggregation are small prefibrillar oligomers. In this review, we describe the recent progress in the characterization of the cellular and molecular interactions by toxic misfolded protein oligomers. A fundamental interaction by these aggregates involves biological membranes, resulting in two major model mechanisms at the onset of the cellular toxicity. These include the membrane disruption model, resulting in calcium imbalance, mitochondrial dysfunction and intracellular reactive oxygen species, and the direct interaction with membrane proteins, leading to the alteration of their native function. A key challenge remains in the characterization of transient interactions involving heterogeneous protein aggregates. Solving this task is crucial in the quest of identifying suitable therapeutic approaches to suppress the cellular toxicity in protein misfolding diseases.

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