Development of the “hidden” multi-target-directed ligands by AChE/BuChE for the treatment of Alzheimer's disease

Chen, Rui; Li, Xinjuan; Chen, Hongsong; Wang, Keren; Xue, Ting; Mi, Jing; Ban, Yujuan; Zhu, Guoqi; Zhou, Yi; Dong, Wu; Tang, Lei; Sang, Zhipei

doi:10.1016/j.ejmech.2023.115253

Cited by 8 publications

(5 citation statements)

References 34 publications

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“…Therefore, the antioxidant activity of the food-derived peptides may treat AD. Moreover, AD is partly caused by the loss of ACh catalyzed by AChE and BuChE [142]. So, antioxidant peptides with inhibition of AChE and BuChE cholinesterase activity or with structures and active centers similar to Ach have more potential for treating AD [143].…”

Section: Antioxidant Peptides In Therapymentioning

confidence: 99%

New Insights into Antioxidant Peptides: An Overview of Efficient Screening, Evaluation Models, Molecular Mechanisms, and Applications

Zhang,

Li,

Quan

et al. 2024

Antioxidants

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Antioxidant peptides are currently a hotspot in food science, pharmaceuticals, and cosmetics. In different fields, the screening, activity evaluation, mechanisms, and applications of antioxidant peptides are the pivotal areas of research. Among these topics, the efficient screening of antioxidant peptides stands at the forefront of cutting-edge research. To this end, efficient screening with novel technologies has significantly accelerated the research process, gradually replacing the traditional approach. After the novel antioxidant peptides are screened and identified, a time-consuming activity evaluation is another indispensable procedure, especially in in vivo models. Cellular and rodent models have been widely used for activity evaluation, whilst non-rodent models provide an efficient solution, even with the potential for high-throughput screening. Meanwhile, further research of molecular mechanisms can elucidate the essence underlying the activity, which is related to several signaling pathways, including Keap1-Nrf2/ARE, mitochondria-dependent apoptosis, TGF-β/SMAD, AMPK/SIRT1/PGC-1α, PI3K/Akt/mTOR, and NF-κB. Last but not least, antioxidant peptides have broad applications in food manufacture, therapy, and the cosmetics industry, which requires a systematic review. This review introduces novel technologies for the efficient screening of antioxidant peptides, categorized with a new vision. A wide range of activity evaluation assays, encompassing cellular models, as well as rodent and non-rodent models, are provided in a comprehensive manner. In addition, recent advances in molecular mechanisms are analyzed with specific cases. Finally, the applications of antioxidant peptides in food production, therapy, and cosmetics are systematically reviewed.

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Section: Antioxidant Peptides In Therapymentioning

confidence: 99%

New Insights into Antioxidant Peptides: An Overview of Efficient Screening, Evaluation Models, Molecular Mechanisms, and Applications

Zhang,

Li,

Quan

et al. 2024

Antioxidants

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“…[3,4] To cure AD, a lot of work on AD has been done, and many causes of disease on AD have been found, including the βamyloid peptide (Aβ) deposition, [5] hyperphosphorylated tauprotein deposition, [6] cholinergic neuronal damage, [7] oxidative stress, [8] and inflammation, [9] et al However, the exact etiology of AD remains elusive. [10,11] Among the reported causes, one of the most widely accepted hypotheses is the cholinergic hypothesis. According to the cholinergic hypothesis, decreased acetylcholine (ACh) levels in specific regions of the brain lead to cognitive and memory impairment in AD.…”

Section: Introductionmentioning

confidence: 99%

“…To cure AD, a lot of work on AD has been done, and many causes of disease on AD have been found, including the β‐amyloid peptide (Aβ) deposition, [5] hyperphosphorylated tau‐protein deposition, [6] cholinergic neuronal damage, [7] oxidative stress, [8] and inflammation, [9] et al. However, the exact etiology of AD remains elusive [10,11] …”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Evaluation of 8‐(Piperazin‐1‐yl) Imidazo[1,2‐a]Pyrazine Derivatives as Acetylcholinesterase Inhibitors and Antioxidants

Wei,

Du,

Guo

et al. 2024

ChemistrySelect

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A series of 8‐(piperazin‐1‐yl) imidazo [1,2‐a] pyrazine derivatives were designed and synthesized as acetylcholinesterase inhibitors (AChEIs) and antioxidants for the treatment of Alzheimer's disease (AD). Moreover, the biological evaluation results demonstrated that these synthesized compounds exhibited moderate inhibitory activities toward acetylcholinesterase (AChE) and radical scavenging activities. Among them, the compound with the strongest inhibitory activity against AChE had an IC50 value of 0.55 μM, which was higher than that of galantamine as the reference compound (IC50 value=5.01 μM). The compound with the strongest antioxidant activity had an IC50 value of 57.94 μM, which was lower than that of the ascorbic acid (IC50 value=25.70 μM) as the control drug. Furthermore, the results of molecular docking studies indicated that the compound could simultaneously bind to both catalytic active site (CAS) and peripheral anionic site (PAS) of AChE, which was consistent with the mixed inhibition pattern shown by enzyme kinetic studies. The interaction's stability was also assessed using a conventional atomistic 100 ns dynamics simulation study, which revealed the conformational stability of representative compound in the cavity of the AChE. In addition, the molecular properties of all compounds were predicted online through the SwissADME, and most compounds matched the properties of most orally administered drugs. Based on the biological activity and molecular properties, 8‐(piperazin‐1‐yl) imidazo[1,2‐a] pyrazine derivatives as AChEI were valuable for further development.

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“…[21][22][23][24][25][26]. On the one hand, the concentration of acetylcholine (ACh) in the synaptic cleft is increased to achieve cognitive improvement [27,28]. On the other hand, it can inhibit the hyperphosphorylation of tau proteins and reduce the accumulation of neurofibrillary tangles (NFTs) [29].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel Tetrahydroacridin Hybrids with Sulfur-Inserted Linkers as Potential Multitarget Agents for Alzheimer’s Disease

Wu,

Ze,

Qin

et al. 2024

Molecules

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Alzheimer’s disease (AD) is a complex neurodegenerative disease that can lead to the loss of cognitive function. The progression of AD is regulated by multiple signaling pathways and their associated targets. Therefore, multitarget strategies theoretically have greater potential for treating AD. In this work, a series of new hybrids were designed and synthesized by the hybridization of tacrine (4, AChE: IC50 = 0.223 μM) with pyrimidone compound 5 (GSK-3β: IC50 = 3 μM) using the cysteamine or cystamine group as the connector. The biological evaluation results demonstrated that most of the compounds exhibited moderate to good inhibitory activities against acetylcholinesterase (AChE) and glycogen synthase kinase 3β (GSK-3β). The optimal compound 18a possessed potent dual AChE/GSK-3β inhibition (AChE: IC50 = 0.047 ± 0.002 μM, GSK-3β: IC50 = 0.930 ± 0.080 μM). Further molecular docking and enzymatic kinetic studies revealed that this compound could occupy both the catalytic anionic site and the peripheral anionic site of AChE. The results also showed a lack of toxicity to SH-SY5Y neuroblastoma cells at concentrations of up to 25 μM. Collectively, this work explored the structure–activity relationships of novel tetrahydroacridin hybrids with sulfur-inserted linkers, providing a reference for the further research and development of new multitarget anti-AD drugs.

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Development of the “hidden” multi-target-directed ligands by AChE/BuChE for the treatment of Alzheimer's disease

Cited by 8 publications

References 34 publications

New Insights into Antioxidant Peptides: An Overview of Efficient Screening, Evaluation Models, Molecular Mechanisms, and Applications

New Insights into Antioxidant Peptides: An Overview of Efficient Screening, Evaluation Models, Molecular Mechanisms, and Applications

Design, Synthesis and Evaluation of 8‐(Piperazin‐1‐yl) Imidazo[1,2‐a]Pyrazine Derivatives as Acetylcholinesterase Inhibitors and Antioxidants

Design, Synthesis, and Biological Evaluation of Novel Tetrahydroacridin Hybrids with Sulfur-Inserted Linkers as Potential Multitarget Agents for Alzheimer’s Disease

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