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Molecular Insights into Drug Development for Alzheimer’s Disease
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Molecular Insights into Drug Development for Alzheimer’s Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 7493

Special Issue Editors

Dr. Zheying Zhu

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Guest Editor
School of Pharmacy, the University of Nottingham, University Park, Nottingham NG7 2RD, UK
Interests: Alzheimer's disease; pre-clinical drug development; gene therapy; drug delivery systems
Prof. Dr. Qiulun Lu

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Guest Editor
State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmaco-kinetics, China Pharmaceutical University, Nanjing, China
Interests: Alzheimer's disease; drug development; gene therapy; neuron damage

Special Issue Information

Dear Colleagues,

Current drug treatments for Alzheimer’s disease are very limited, with only four inhibitors of neurotransmitters on the market to relieve the symptoms of the condition. With the failure of a number of monoclonal antibodies targeting Aβ over the past decades, the first monoclonal antibody, Lecanemab (Aduhelm®), was approved by the FDA in 2022, albeit it is continuing to undergo phase III clinical trials. Therefore, the discovery and development of novel disease-modifying drugs for the treatment of Alzheimer’s disease is a hugely unmet clinical need. This Special Issue will provide a platform for researchers to share their research findings and present a broad range of topics relevant to any stage of drug development for the treatment of Alzheimer’s disease. In particular, we warmly welcome contributions on the latest developments in the following topics: novel drug target and validation, the discovery and development of novel drug candidates, including small molecules and biologics, drug repurposing, gene therapy, advanced drug delivery systems, and pre-clinical models for drug evaluation. The Special Issue calls for original research, reviews, and short communications that address the progress and identify any knowledge gap at a molecular level in the drug development of Alzheimer’s disease.

Dr. Zheying Zhu
Prof. Dr. Qiulun Lu
Guest Editors

Manuscript Submission Information

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Keywords

  • Alzheimer’s disease
  • drug targets
  • repurposing
  • biologics
  • gene therapy
  • delivery systems
  • pre-clinical models

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Published Papers (3 papers)

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Research

20 pages, 7816 KiB  
Article
Targeting Alzheimer’s Disease: Evaluating the Efficacy of C-1 Functionalized N-Aryl-Tetrahydroisoquinolines as Cholinergic Enzyme Inhibitors and Promising Therapeutic Candidates
by Dunja Jovanović, Ana Filipović, Goran Janjić, Tamara Lazarević-Pašti, Zdravko Džambaski, Bojan P. Bondžić and Aleksandra M. Bondžić
Int. J. Mol. Sci. 2024, 25(2), 1033; https://doi.org/10.3390/ijms25021033 - 14 Jan 2024
Cited by 4 | Viewed by 1796
Abstract
We have synthesized 22 C-1 functionalized-N-aryl-1,2,3,4-tetrahydroisoquinoline derivatives showing biological activities towards cholinergic enzymes. Synthesis was performed using visible-light-promoted photo-redox chemistry, starting from a common intermediate, and the application of this synthetic methodology drastically simplified synthetic routes and purification of desired compounds. [...] Read more.
We have synthesized 22 C-1 functionalized-N-aryl-1,2,3,4-tetrahydroisoquinoline derivatives showing biological activities towards cholinergic enzymes. Synthesis was performed using visible-light-promoted photo-redox chemistry, starting from a common intermediate, and the application of this synthetic methodology drastically simplified synthetic routes and purification of desired compounds. All synthesized derivates were divided into four groups based on the substituents in the C-1 position, and their inhibition potencies towards two cholinergic enzymes, acetyl- and butyrylcholinesterase were evaluated. Most potent derivatives were selected, and kinetic analysis was further carried out to obtain insights into the mechanisms of inhibition of these two enzymes. Further validation of the mode of inhibition of cholinergic enzymes by the two most potent THIQ compounds, 3c and 3i, was performed using fluorescence-quenching titration studies. Molecular docking studies further confirmed the proposed mechanism of enzymes’ inhibition. In silico predictions of physicochemical properties, pharmacokinetics, drug-likeness, and medicinal chemistry friendliness of the selected most potent derivatives were performed using Swiss ADME tool. This was followed by UPLC-assisted log P determination and in vitro BBB permeability studies performed in order to assess the potential of the synthesized compounds to pass the BBB. Full article
(This article belongs to the Special Issue Molecular Insights into Drug Development for Alzheimer’s Disease)
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13 pages, 5538 KiB  
Article
Asiaticoside Mitigates Alzheimer’s Disease Pathology by Attenuating Inflammation and Enhancing Synaptic Function
by Sai Liu, Long Chen, Jinran Li, Yuan Sun, Yue Xu, Zhaoxing Li, Zheying Zhu and Xinuo Li
Int. J. Mol. Sci. 2023, 24(15), 11976; https://doi.org/10.3390/ijms241511976 - 26 Jul 2023
Cited by 10 | Viewed by 2390
Abstract
Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder, hallmarked by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles. Due to the uncertainty of the pathogenesis of AD, strategies aimed at suppressing neuroinflammation and fostering synaptic repair are eagerly sought. Asiaticoside (AS), a [...] Read more.
Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder, hallmarked by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles. Due to the uncertainty of the pathogenesis of AD, strategies aimed at suppressing neuroinflammation and fostering synaptic repair are eagerly sought. Asiaticoside (AS), a natural triterpenoid derivative derived from Centella asiatica, is known for its anti-inflammatory, antioxidant, and wound-healing properties; however, its neuroprotective function in AD remains unclear. Our current study reveals that AS, when administered (40 mg/kg) in vivo, can mitigate cognitive dysfunction and attenuate neuroinflammation by inhibiting the activation of microglia and proinflammatory factors in Aβ1-42-induced AD mice. Further mechanistic investigation suggests that AS may ameliorate cognitive impairment by inhibiting the activation of the p38 MAPK pathway and promoting synaptic repair. Our findings propose that AS could be a promising candidate for AD treatment, offering neuroinflammation inhibition and enhancement of synaptic function. Full article
(This article belongs to the Special Issue Molecular Insights into Drug Development for Alzheimer’s Disease)
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15 pages, 1637 KiB  
Article
Positive Allosteric Modulator of SERCA Pump NDC-1173 Exerts Beneficial Effects in Mouse Model of Alzheimer’s Disease
by Russell Dahl, Amanda C. Moore, Caitlynn Knight, Colleen Mauger, Hua Zhang, Gary E. Schiltz, Wendy A. Koss and Ilya Bezprozvanny
Int. J. Mol. Sci. 2023, 24(13), 11057; https://doi.org/10.3390/ijms241311057 - 4 Jul 2023
Cited by 9 | Viewed by 2736
Abstract
Alzheimer’s disease (AD) is an irreversible neurodegenerative disease that affects millions of people worldwide. AD does not have a cure and most drug development efforts in the AD field have been focused on targeting the amyloid pathway based on the “amyloid cascade hypothesis”. [...] Read more.
Alzheimer’s disease (AD) is an irreversible neurodegenerative disease that affects millions of people worldwide. AD does not have a cure and most drug development efforts in the AD field have been focused on targeting the amyloid pathway based on the “amyloid cascade hypothesis”. However, in addition to the amyloid pathway, substantial evidence also points to dysregulated neuronal calcium (Ca2+) signaling as one of the key pathogenic events in AD, and it has been proposed that pharmacological agents that stabilize neuronal Ca2+ signaling may act as disease-modifying agents in AD. In previous studies, we demonstrated that positive allosteric regulators (PAMs) of the Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) pump might act as such Ca2+ stabilizing agents. In the present study, we report the development of a novel SERCA PAM agent, compound NDC-1173. To test the effectiveness of this compound, we performed behavioral studies with the APP/PS1 transgenic AD mouse model. We also evaluated effects of this compound on expression of endoplasmic reticulum (ER) stress genes in the hippocampus of APP/PS1 mice. The results of this study support the hypothesis that the SERCA pump is a potential novel therapeutic drug target and that NDC-1173 is a promising lead molecule for developing disease-modifying agents in AD. Full article
(This article belongs to the Special Issue Molecular Insights into Drug Development for Alzheimer’s Disease)
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