Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

Chemical Reviews, Год журнала: 2021, Номер 121(4), С. 2545 - 2647

Опубликована: Фев. 5, 2021

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural dynamic characterization all species along pathways from monomers to fibrils challenging by experimental computational means because they involve intrinsically disordered proteins most diseases. Yet understanding how amyloid become toxic challenge developing treatment for these Here we review what computer, vitro, vivo, pharmacological experiments tell us about accumulation deposition oligomers (Aβ, tau), α-synuclein, IAPP, superoxide dismutase 1 proteins, which have been mainstream concept underlying Alzheimer's disease (AD), Parkinson's (PD), type II diabetes (T2D), amyotrophic lateral sclerosis (ALS) research, respectively, years.

Язык: Английский

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Development of Multifunctional Molecules as Potential Therapeutic Candidates for Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis in the Last Decade

Chemical Reviews, Год журнала: 2018, Номер 119(2), С. 1221 - 1322

Опубликована: Авг. 10, 2018

Neurodegenerative diseases pose a substantial socioeconomic burden on society. Unfortunately, the aging world population and lack of effective cures foreshadow negative outlook. Although large amount research has been dedicated to elucidating pathologies neurodegenerative diseases, their principal causes remain elusive. Metal ion dyshomeostasis, proteopathy, oxidative stress, neurotransmitter deficiencies are pathological features shared across multiple disorders. In addition, these factors proposed be interrelated upon disease progression. Thus, development multifunctional compounds capable simultaneously interacting with several components suggested as solution undertake complex diseases. this review, we outline discuss possible therapeutic targets in Alzheimer's disease, Parkinson's amyotrophic lateral sclerosis molecules, previously designed or discovered potential drug candidates for disorders emphasis multifunctionality. underrepresented areas discussed indicate new directions.

Язык: Английский

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8-Hydroxyquinolines in medicinal chemistry: A structural perspective

European Journal of Medicinal Chemistry, Год журнала: 2016, Номер 120, С. 252 - 274

Опубликована: Май 6, 2016

Язык: Английский

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Rational Design of Multitarget-Directed Ligands: Strategies and Emerging Paradigms

Journal of Medicinal Chemistry, Год журнала: 2019, Номер 62(20), С. 8881 - 8914

Опубликована: Май 13, 2019

Due to the complexity of multifactorial diseases, single-target drugs do not always exhibit satisfactory efficacy. Recently, increasing evidence indicates that simultaneous modulation multiple targets may improve both therapeutic safety and efficacy, compared with drugs. However, few multitarget are on market or in clinical trials, despite best efforts medicinal chemists. This article discusses systematic establishment target combination, lead generation, optimization multitarget-directed ligands (MTDLs). Moreover, we analyze some MTDLs research cases for several complex diseases recent years physicochemical properties 117 drugs, aim reveal trends insights potential use MTDLs.

Язык: Английский

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Interrogating Amyloid Aggregates using Fluorescent Probes

Chemical Reviews, Год журнала: 2019, Номер 119(23), С. 11819 - 11856

Опубликована: Ноя. 1, 2019

Amyloids are a broad class of proteins and peptides that can misfold assemble into long unbranched fibrils with cross-β conformation. These misfolding aggregation events associated the onset variety human diseases, among them, Alzheimer's disease, Parkinson's Huntington disease. Our understanding amyloids has been greatly supported by fluorescent molecular probes, such as thioflavin-T, which shows an increase in fluorescence emission upon binding to fibrillar aggregates. Since first application thioflavin-T amyloid studies nearly 30 years ago, many probes have emerged exhibiting responses amyloids, intensity changes, shifts maxima, variations lifetimes, others. shed light on topics including kinetics aggregation, effectiveness inhibitors, elucidation sites structures, staining aggregates vitro, ex vivo, vivo. In this Review, we discuss design, properties, photoactive used study well challenges faced current techniques, novel approaches emerging address these challenges.

Язык: Английский

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Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease

Chemical Communications, Год журнала: 2015, Номер 51(70), С. 13434 - 13450

Опубликована: Янв. 1, 2015

Our Feature Article details the physiological role of amyloid beta (Aβ), elaborates its toxic effects and outlines therapeutic molecules designed in last two years targeting different aspects Aβ for preventing AD.

Язык: Английский

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Alzheimer's disease: Updated multi-targets therapeutics are in clinical and in progress

European Journal of Medicinal Chemistry, Год журнала: 2022, Номер 238, С. 114464 - 114464

Опубликована: Май 20, 2022

Язык: Английский

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Metal complexes designed to bind to amyloid-β for the diagnosis and treatment of Alzheimer's disease

Chemical Society Reviews, Год журнала: 2014, Номер 43(19), С. 6701 - 6715

Опубликована: Янв. 1, 2014

The use radioactive copper and technetium complexes as amyloid imaging agents, the of luminescent metal non-conventional probes formation potential to be inhibitors toxicity are discussed.

Язык: Английский

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The Ongoing Search for Small Molecules to Study Metal-Associated Amyloid-β Species in Alzheimer’s Disease

Accounts of Chemical Research, Год журнала: 2014, Номер 47(8), С. 2475 - 2482

Опубликована: Июль 31, 2014

The development of a cure for Alzheimer's disease (AD) has been impeded by an inability to pinpoint the root cause this disorder. Although numerous potential pathological factors have indicated, acting either individually or mutually, molecular mechanisms leading onset and progression not clear. Amyloid-β (Aβ), generated from proteolytic processing amyloid precursor protein (APP), its aggregated forms, particularly oligomers, are suggested as key features in AD-affected brains. Historically, highly concentrated metals found colocalized within Aβ plaques. Metal binding (metal-Aβ) generates/stabilizes potentially toxic produces reactive oxygen species (ROS) vitro (redox active metal ions; plausible contribution oxidative stress). Consequently, clarification relationship between Aβ, ions, toxicity, including stress via metal-Aβ, can lead deeper understanding AD development. To probe involvement metal-Aβ pathogenesis, rationally designed naturally occurring molecules examined chemical tools target species, modulate interaction subsequently redirect their aggregation into nontoxic, off-pathway unstructured aggregates. These ligands also capable attenuating generation redox metal-Aβ-induced ROS mitigate stress. One rational design concept, incorporation approach, installs site framework known interact with Aβ. This approach affords compounds simultaneous ability chelate ions Natural products investigated influence on metal-induced inspired construction synthetic analogues. Systematic studies these natural could uncover relationships structures, metal/Aβ/metal-Aβ interactions, inhibition Aβ/metal-Aβ reactivity (i.e., modes Aβ/metal-Aβ; associated production), suggesting refine strategy. Interdisciplinary investigations demonstrated that control pathways transforming size/conformation distribution. aptitude impact pathways, aggregate formation, most importantly disaggregation preformed fibrils, originate formation complexes metal-Aβ. Potentially, direct size/conformational states alternative nontoxic geometry at Aβ-ligated center limited lessen overall toxicity induced Complexation small observed nuclear magnetic resonance spectroscopy (NMR) ion mobility-mass spectrometry (IM-MS) pointing level validating In addition, exhibit other attractive properties, such antioxidant capacity, prevention production, blood-brain barrier (BBB) permeability, reduction Aβ-/metal-Aβ-induced cytotoxicity, making them desirable unraveling complexity. Account, we summarize recent molecules, both selection modification products, investigating complexes, advance our relation pathology.

Язык: Английский

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Alzheimer’s disease: How metal ions define β-amyloid function

Coordination Chemistry Reviews, Год журнала: 2017, Номер 351, С. 127 - 159

Опубликована: Май 20, 2017

Язык: Английский

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