scholarly journals Catechol-Containing Compounds are a Broad Class of Protein Aggregation Inhibitors: Redox State is a Key Determinant of the Inhibitory Activities

2020 ◽  
Author(s):  
Paul Velander ◽  
Ling Wu ◽  
Sherry B. Hildreth ◽  
Nancy J. Vogelaar ◽  
Biswarup Mukhopadhyay ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Small Molecule ◽  
Rational Design ◽  
Redox State ◽  
Broad Class ◽  
Intrinsically Disordered ◽  
Amyloidogenic Proteins ◽  
Key Factor ◽  
Inhibitory Activities ◽  
Screening Platform

Abstract Background: A range of neurodegenerative and related aging diseases, such as Alzheimer’s disease, Parkinson’s disease, and type 2 diabetes, are linked to toxic protein aggregation. Yet the mechanisms of protein aggregation inhibition by small molecule inhibitors remain poorly understood, in part because most protein targets of aggregation assembly are partially unfolded or intrinsically disordered, which hinders detailed structural characterization of protein-inhibitor complexes and structural-based mechanistic elucidation. Methods: Herein we employed a small molecule screening approach to identify inhibitors against three prototype amyloidogenic proteins in neurodegeneration and related proteinopathies: amylin, Ab and tau. We further systematically investigated selected class of inhibitors under aerobic and anaerobic conditions to uncover a key determinant of the inhibitory activities.Results: One remarkable class of inhibitors identified from all three parallel screenings against different amyloidogenic proteins was catechol-containing compounds and redox-related quinones/anthraquinones. Further mechanistic studies determined that the redox state of the broad class of catechol-containing compounds is a key determinant of the amyloid inhibitor activities. Conclusion: Our small molecule library screening platform was able to identify a broad class of amyloid inhibitors. Redox was found to be a key factor not only regulating the inhibitory activities but also involving the mechanism of inhibition. The molecular insights we gained not only explain why a large number of catechol-containing natural compounds, often enriched in healthy diet, have anti-neurodegeneration and anti-aging activities, but also could guide the rational design of therapeutic or nutraceutical strategies to target a broad range of neurodegenerative and related aging diseases.

scholarly journals Catechol-Containing Compounds are a Broad Class of Amyloid Inhibitors: Redox State is a Key Determinant of the Inhibitory Activities

2020 ◽  
Author(s):  
Paul Velander ◽  
Ling Wu ◽  
Sherry B. Hildreth ◽  
Nancy J. Vogelaar ◽  
Biswarup Mukhopadhyay ◽  
...  
Keyword(s):  
Redox State ◽  
Broad Class ◽  
Protein Inhibitor ◽  
Protein Targets ◽  
Intrinsically Disordered ◽  
Amyloidogenic Proteins ◽  
Small Molecule Screening ◽  
Partially Unfolded ◽  
Amyloid Assembly

ABSTRACTMechanisms of amyloid inhibition remains poorly understood, in part because most protein targets of amyloid assembly are partially unfolded or intrinsically disordered, which hinders detailed structural characterization of protein-inhibitor complexes and structural-based mechanistic elucidation. Herein we employed a small molecule screening approach to identify inhibitors against three prototype amyloidogenic proteins: amylin, Aβ and tau. One remarkable class of inhibitors identified was catechol-containing compounds and redox-related quinones/anthraquinones. Further mechanistic studies determined that the redox state of the broad class of catechol-containing compounds is a key determinant of the amyloid inhibitor activities.

scholarly journals Molecular basis of small-molecule binding to α-synuclein

2021 ◽  
Author(s):  
Paul Robustelli ◽  
Alain Ibanez-de-Opakua ◽  
Cecily Campbell-Bezat ◽  
Fabrizio Giordanetto ◽  
Stefan Becker ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Rational Design ◽  
Intrinsically Disordered Proteins ◽  
Md Simulations ◽  
Structural Features ◽  
Atomic Level ◽  
Disordered Proteins ◽  
Structure Based Drug Design ◽  
Intrinsically Disordered

AbstractIntrinsically disordered proteins (IDPs) are implicated in many human diseases. They have generally not been amenable to conventional structure-based drug design, however, because their intrinsic conformational variability has precluded an atomic-level understanding of their binding to small molecules. Here we present long-timescale, atomic-level molecular dynamics (MD) simulations of monomeric α-synuclein (an IDP whose aggregation is associated with Parkinson’s disease) binding the small-molecule drug fasudil in which the observed protein-ligand interactions were found to be in good agreement with previously reported NMR chemical shift data. In our simulations, fasudil, when bound, favored certain charge-charge and π-stacking interactions near the C terminus of α-synuclein, but tended not to form these interactions simultaneously, rather breaking one of these interactions and forming another nearby (a mechanism we term dynamic shuttling). Further simulations with small molecules chosen to modify these interactions yielded binding affinities and key structural features of binding consistent with subsequent NMR experiments, suggesting the potential for MD-based strategies to facilitate the rational design of small molecules that bind with disordered proteins.

scholarly journals Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lars Plate ◽  
Christina B Cooley ◽  
John J Chen ◽  
Ryan J Paxman ◽  
Ciara M Gallagher ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Small Molecule ◽  
Protein Misfolding ◽  
Transcriptional Profiling ◽  
Extracellular Protein ◽  
Unfolded Protein ◽  
Amyloidogenic Proteins ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Protein Misfolding And Aggregation

Imbalances in endoplasmic reticulum (ER) proteostasis are associated with etiologically-diverse degenerative diseases linked to excessive extracellular protein misfolding and aggregation. Reprogramming of the ER proteostasis environment through genetic activation of the Unfolded Protein Response (UPR)-associated transcription factor ATF6 attenuates secretion and extracellular aggregation of amyloidogenic proteins. Here, we employed a screening approach that included complementary arm-specific UPR reporters and medium-throughput transcriptional profiling to identify non-toxic small molecules that phenocopy the ATF6-mediated reprogramming of the ER proteostasis environment. The ER reprogramming afforded by our molecules requires activation of endogenous ATF6 and occurs independent of global ER stress. Furthermore, our molecules phenocopy the ability of genetic ATF6 activation to selectively reduce secretion and extracellular aggregation of amyloidogenic proteins. These results show that small molecule-dependent ER reprogramming, achieved through preferential activation of the ATF6 transcriptional program, is a promising strategy to ameliorate imbalances in ER function associated with degenerative protein aggregation diseases.

scholarly journals Impact of porous nanomaterials on inhibiting protein aggregation behaviour

RSC Advances ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 3354-3362
Author(s):  
Munmun Bardhan ◽  
Sandip Dolui ◽  
Siddhi Chaudhuri ◽  
Uttam Paul ◽  
Gaurav Bhattacharjee ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Physiological Conditions ◽  
Intrinsically Disordered ◽  
Aggregation Behaviour ◽  
Inhibiting Protein ◽  
Porous Nanomaterials

Aggregation of intrinsically disordered as well as the ordered proteins under certain premises or physiological conditions leads to pathological disorder.

scholarly journals Binding Ensembles of p53-MDM2 Peptide Inhibitors by Combining Bayesian Inference and Atomistic Simulations

Molecules ◽  
2021 ◽  
Vol 26 (1) ◽  
pp. 198
Author(s):  
Lijun Lang ◽  
Alberto Perez
Keyword(s):  
Bayesian Inference ◽  
Virtual Screening ◽  
Statistical Mechanics ◽  
Small Molecules ◽  
Rational Design ◽  
Driving Forces ◽  
Peptide Inhibitors ◽  
Atomistic Simulations ◽  
Binding Mechanism ◽  
Intrinsically Disordered

Designing peptide inhibitors of the p53-MDM2 interaction against cancer is of wide interest. Computational modeling and virtual screening are a well established step in the rational design of small molecules. But they face challenges for binding flexible peptide molecules that fold upon binding. We look at the ability of five different peptides, three of which are intrinsically disordered, to bind to MDM2 with a new Bayesian inference approach (MELD × MD). The method is able to capture the folding upon binding mechanism and differentiate binding preferences between the five peptides. Processing the ensembles with statistical mechanics tools depicts the most likely bound conformations and hints at differences in the binding mechanism. Finally, the study shows the importance of capturing two driving forces to binding in this system: the ability of peptides to adopt bound conformations (ΔGconformation) and the interaction between interface residues (ΔGinteraction).

Construction of lux-based promoter-reporter platforms in Mycobacterium bovis BCG for screening of drug repurposing small-molecule compounds as new anti-tuberculosis drugs

2021 ◽  
Author(s):  
Li Zhu ◽  
Annie Wing-tung Lee ◽  
Kelvin Ka-Lok WU ◽  
Peng GAO ◽  
Kingsley King-Gee Tam ◽  
...  
Keyword(s):  
Small Molecule ◽  
Drug Repurposing ◽  
Virulence Gene ◽  
Multidrug Resistant ◽  
Rapid Screening ◽  
Human Macrophage ◽  
Tuberculosis Complex ◽  
Low Cytotoxicity ◽  
Screening Platform

The emergence of multidrug-resistant strains and hyper-virulent strains of Mycobacterium tuberculosis are big therapeutic challenges for tuberculosis (TB) control. Repurposing bioactive small-molecule compounds has recently become a new therapeutic approach against TB. This study aimed to construct a rapid screening system to identify novel anti-TB agents from a library of small-molecule compounds. In this study, a total of 320 small-molecule compounds were used to screen for their ability to suppress the expression of a key virulence gene, phoP, of M. tuberculosis complex using luminescence (lux)-based promoter-reporter platforms. The minimum inhibitory and bactericidal concentrations on drug-resistant M. tuberculosis and cytotoxicity to human macrophage were determined. RNA-sequencing (RNA-seq) was conducted to determine the drug mechanisms of the selected compounds as novel antibiotics or anti-virulent agents against the M. tuberculosis complex. Six compounds displayed bactericidal activity against M. bovis BCG, in which Ebselen demonstrated the lowest cytotoxicity to macrophage and was considered as a potential antibiotic for TB. Another ten compounds did not inhibit the in vitro growth of the M. tuberculosis complex but down-regulated the expression of phoP specifically. Of them, ST-193 and ST-193 (hydrochloride) showed low cytotoxicity and could dysregulate the entire phoP-associated gene network, and thus identified as potential anti-virulence agents for M. tuberculosis. This study provides a rapid screening platform coupled with a systematic validation and eventually suggested one potential antibiotic and two anti-virulence agents for M. tuberculosis infections.

scholarly journals A journey in bioinspired supramolecular chemistry: from molecular tweezers to small molecules that target myotonic dystrophy

2016 ◽  
Vol 12 ◽  
pp. 125-138 ◽  
Author(s):  
Steven C Zimmerman
Keyword(s):  
Small Molecules ◽  
Supramolecular Chemistry ◽  
Myotonic Dystrophy ◽  
Small Molecule ◽  
Early Life ◽  
Rational Design ◽  
Early Experience ◽  
Therapeutic Agents ◽  
Early Career ◽  
Molecular Tweezers

This review summarizes part of the author’s research in the area of supramolecular chemistry, beginning with his early life influences and early career efforts in molecular recognition, especially molecular tweezers. Although designed to complex DNA, these hosts proved more applicable to the field of host–guest chemistry. This early experience and interest in intercalation ultimately led to the current efforts to develop small molecule therapeutic agents for myotonic dystrophy using a rational design approach that heavily relies on principles of supramolecular chemistry. How this work was influenced by that of others in the field and the evolution of each area of research is highlighted with selected examples.

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