Amyloid-β and tau aggregation dual-inhibitors: A synthetic and structure-activity relationship focused review

Malafaia, Daniela; Albuquerque, Hélio M. T.; Silva, Artur M. S.

doi:10.1016/j.ejmech.2021.113209

Cited by 35 publications

(31 citation statements)

References 73 publications

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“…To the best of our knowledge, the activity of these compounds is higher than that of multifunctional ligands reported to date. 10 Among the tested derivatives, we selected compound 18 , which exhibited a unique profile of biological activity. This compound is the most potent and balanced dual aggregation inhibitor (Aβ 42 inh.…”

Section: Discussionmentioning

confidence: 99%

Dual Inhibitors of Amyloid-β and Tau Aggregation with Amyloid-β Disaggregating Properties: Extended In Cellulo, In Silico, and Kinetic Studies of Multifunctional Anti-Alzheimer’s Agents

Pasieka

Panek

Szałaj

et al. 2021

ACS Chem. Neurosci.

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In Alzheimer’s disease, neurons slowly degenerate due to the accumulation of misfolded amyloid β and tau proteins. In our research, we performed extended studies directed at amyloid β and tau aggregation inhibition using in cellulo ( Escherichia coli model of protein aggregation), in silico , and in vitro kinetic studies. We tested our library of 1-benzylamino-2-hydroxyalkyl multifunctional anti-Alzheimer’s agents and identified very potent dual aggregation inhibitors. Among the tested derivatives, we selected compound 18 , which exhibited a unique profile of biological activity. This compound was the most potent and balanced dual aggregation inhibitor (Aβ 42 inhibition (inh.) 80.0%, tau inh. 68.3% in 10 μM), with previously reported in vitro inhibitory activity against h BuChE, h BACE1, and Aβ ( h BuChE IC 50 = 5.74 μM; h BACE1 IC 50 = 41.6 μM; Aβ aggregation (aggr.) inh. IC 50 = 3.09 μM). In docking studies for both proteins, we tried to explain the different structural requirements for the inhibition of Aβ vs tau. Moreover, docking and kinetic studies showed that compound 18 could inhibit the amyloid aggregation process at several steps and also displayed disaggregating properties. These results may help to design the next generations of dual or selective aggregation inhibitors.

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Section: Discussionmentioning

confidence: 99%

Dual Inhibitors of Amyloid-β and Tau Aggregation with Amyloid-β Disaggregating Properties: Extended In Cellulo, In Silico, and Kinetic Studies of Multifunctional Anti-Alzheimer’s Agents

Pasieka

Panek

Szałaj

et al. 2021

ACS Chem. Neurosci.

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“…Indeed, a large number of multitarget compounds feature pharmacophoric moieties of the approved AChE inhibitors [ 29 , 30 , 31 , 32 ], even though publications on multitarget anti-AD agents based on other pharmacophores, especially naturally occurring scaffolds such as β-carbolines [ 33 ], naphthoquinones and anthraquinones [ 34 ], or chalcones [ 35 ], just to name a few of those recently reviewed, are continuously appearing. Apart from AChE, other targets and pathogenic mechanisms that, intuitively, seem to have been commonly addressed when designing multitarget anti-AD compounds are glutamante NMDA receptors [ 36 , 37 ], β-amyloid and tau aggregation [ 38 , 39 ], glycogen synthase kinase 3β (GSK-3β) [ 40 ], biometal dyshomeostasis [ 41 ], monoamine oxidases (MAOs) [ 42 ], or oxidative stress [ 43 ]. It is usually assumed that the linked-pharmacophore strategy is the most popular design strategy, likely because AChE is thought to be the most commonly pursued target in multitarget anti-AD drug design and it is one of those proteins with binding sites buried at the bottom of a deep cavity.…”

Section: Introductionmentioning

confidence: 99%

Unveiling the Multitarget Anti-Alzheimer Drug Discovery Landscape: A Bibliometric Analysis

et al. 2022

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Multitarget anti-Alzheimer agents are the focus of very intensive research. Through a comprehensive bibliometric analysis of the publications in the period 1990–2020, we have identified trends and potential gaps that might guide future directions. We found that: (i) the number of publications boomed by 2011 and continued ascending in 2020; (ii) the linked-pharmacophore strategy was preferred over design approaches based on fusing or merging pharmacophores or privileged structures; (iii) a significant number of in vivo studies, mainly using the scopolamine-induced amnesia mouse model, have been performed, especially since 2017; (iv) China, Italy and Spain are the countries with the largest total number of publications on this topic, whereas Portugal, Spain and Italy are the countries in whose scientific communities this topic has generated greatest interest; (v) acetylcholinesterase, β-amyloid aggregation, oxidative stress, butyrylcholinesterase, and biometal chelation and the binary combinations thereof have been the most commonly pursued, while combinations based on other key targets, such as tau aggregation, glycogen synthase kinase-3β, NMDA receptors, and more than 70 other targets have been only marginally considered. These results might allow us to spot new design opportunities based on innovative target combinations to expand and diversify the repertoire of multitarget drug candidates and increase the likelihood of finding effective therapies for this devastating disease.

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“…Amyloid fibrils derived from different polypeptides show indeed common properties and structure regardless of the aminoacidic sequence, and this is one of the reasons why well-known proteins like lysozyme can be considered a good model for amyloid research, too [8]. Many studies have been devoted to investigate the fibril formation mechanism [9] and to identify natural [10,11] or synthetic compounds effective as antiamyloid agents [12][13][14]. Among naturally occurring molecules, osmolytes are increasingly investigated as potential therapeutic tools against amyloidogenic disorders [15].…”

Section: Introductionmentioning

confidence: 99%

Taurine Stabilizing Effect on Lysozyme

Mastrella

Moretti

Pieraccini

et al. 2022

Life

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Taurine is an important organic osmolyte in mammalian cells, and it weakens inflammation and oxidative stress mediated injuries in some diseases. Recently, taurine has been demonstrated to play a therapeutic role against neurodegenerative disorders, although its parallel involvement in several biochemical mechanisms makes not clear taurine specific role in these diseases. Furthermore, the stabilizing effect of this molecule in terms of protein stability is known, but not deeply investigated. In this work we explore by Circular Dichroism the stabilizing impact of taurine in lysozyme thermal denaturation and its influence in lysozyme aggregation into amyloid fibrils. Taurine even at low concentration modifies protein-protein interactions in lysozyme native state, as revealed by Small Angle X-ray Scattering experiments, and alters the amyloid aggregation pattern without completely inhibiting it, as confirmed by UV/Vis spectroscopy with Congo Red and by Atomic Force Microscopy. Evaluation of the cytotoxicities of the amyloid fibrils grown in presence or in absence of taurine is investigated on SH-SY5Y neuroblastoma cells.

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Amyloid-β and tau aggregation dual-inhibitors: A synthetic and structure-activity relationship focused review

Cited by 35 publications

References 73 publications

Dual Inhibitors of Amyloid-β and Tau Aggregation with Amyloid-β Disaggregating Properties: Extended In Cellulo, In Silico, and Kinetic Studies of Multifunctional Anti-Alzheimer’s Agents

Dual Inhibitors of Amyloid-β and Tau Aggregation with Amyloid-β Disaggregating Properties: Extended In Cellulo, In Silico, and Kinetic Studies of Multifunctional Anti-Alzheimer’s Agents

Unveiling the Multitarget Anti-Alzheimer Drug Discovery Landscape: A Bibliometric Analysis

Taurine Stabilizing Effect on Lysozyme

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