Article
Biochemistry & Molecular Biology
Kamila Czarnecka, Malgorzata Girek, Pawel Krecisz, Robert Skibinski, Kamil Latka, Jakub Jonczyk, Marek Bajda, Piotr Szymczyk, Grzegorz Galita, Jacek Kabzinski, Ireneusz Majsterek, Alba Espargaro, Raimon Sabate, Pawel Szymanski
Summary: Alzheimer's disease (AD) is a progressive neurodegenerative brain disease and current drugs are not entirely effective in its treatment. This study evaluated eight derivatives as candidates for stronger anti-AD potential with fewer side effects. Compound 3e displayed moderate inhibition of cholinesterase and significant inhibition of A beta aggregation, indicating promise as a potential new anti-AD drug.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2023)
Article
Neurosciences
Pan Liu, Qian Yang, Ning Yu, Yan Cao, Xue Wang, Zhao Wang, Wen-Ying Qiu, Chao Ma
Summary: Metabolomics analysis of postmortem human brain tissues revealed pervasive metabolic dysregulation, including abnormalities in phenylalanine metabolism, valine, leucine, and isoleucine biosynthesis, and other pathways, in the hippocampus of individuals with Alzheimer's disease (AD). The study identified upregulation of specific metabolites and enzymes associated with AD pathology, pointing towards a potential role of phenylalanine metabolism dysregulation in the formation of AD pathology.
JOURNAL OF ALZHEIMERS DISEASE
(2021)
Article
Biochemistry & Molecular Biology
Danuta Drozdowska, Dawid Maliszewski, Agnieszka Wrobel, Artur Ratkiewicz, Michal Sienkiewicz
Summary: Eleven new benzamides were synthesized and one derivative showed the strongest inhibitory activity against acetylcholinesterase and beta-secretase. Molecular modeling revealed that the compound increased the enzyme's stiffness and reduced its flexibility to inhibit the enzyme.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Neurosciences
Heba M. Mansour, Hala M. Fawzy, Aiman S. El-Khatib, Mahmoud M. Khattab
Summary: The study explores the potential of EGFR-TKIs in treating AD, finding that LAP can improve cognitive decline and mitigate pathological alterations by activating pro-survival pathways such as PI3K-Akt-GSK-3β, while inhibiting p-mTOR, NOX-1, and p38 MAPK pathways.
EXPERIMENTAL NEUROLOGY
(2021)
Review
Pharmacology & Pharmacy
Yu Li, Yuanyuan Zhao, Xiaona Li, Liuqun Zhai, Hua Zheng, Ying Yan, Qiang Fu, Jinlian Ma, Haier Fu, Zhenqiang Zhang, Zhonghua Li
Summary: Alzheimer's disease is a common neurodegenerative disease with no cure. Lysine-specific demethylase 1 (LSD1) plays an important role in the pathogenesis of AD and has potential therapeutic benefits for treatment.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Tereza Cristina Santos Evangelista, Oscar Lopez, Adrian Puerta, Miguel X. Fernandes, Sabrina Baptista Ferreira, Jose M. Padron, Jose G. Fernandez-Bolanos, Magne O. Sydnes, Emil Lindback
Summary: The synthesis of four heterodimers connecting a 1-deoxynojirimycin moiety with a benzotriazole scaffold using the copper(I)-catalysed azide-alkyne cycloaddition was reported. These heterodimers showed preferential inhibition against butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE) in the micromolar concentration range. The most potent inhibitor of BuChE demonstrated a mixed inhibition mode, with the benzotriazole and 1-deoxynojirimycin moiety accommodated in the catalytic anionic site and peripheral anionic site of AChE, respectively. However, the binding mode to BuChE was different, with the benzotriazole moiety accommodated in the catalytic anionic site.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Raquel B. M. de Almeida, Deyse B. B. Barbosa, Mayra R. R. do Bomfim, Jessika A. O. Amparo, Bruno S. S. Andrade, Silvia L. L. Costa, Joaquin M. Campos, Jorddy N. Cruz, Cleydson B. R. Santos, Franco H. A. Leite, Mariana B. B. Botura
Summary: The compound ZINC390718 was found to exhibit inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and showed low cytotoxicity in vitro. Molecular dynamics (MD) simulation revealed that ZINC390718 interacted with the catalytic residue sites of both enzymes. These findings suggest that ZINC390718 could be a potential chemotype for the development of new dual cholinesterase inhibitors.
Article
Chemistry, Multidisciplinary
Nan Gao, Zhenqi Liu, Haochen Zhang, Chun Liu, Dongqin Yu, Jinsong Ren, Xiaogang Qu
Summary: Post-translational modification (PTM) can alter protein conformation and function. In this study, a new approach using chemical PTM modification to inhibit amyloid aggregation was presented. Polyoxometalates (POMs) were used as inhibitors and the superiority of the chemical PTM method was demonstrated through various techniques.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Review
Biochemistry & Molecular Biology
Dajiang Zou, Renzheng Liu, Yangjing Lv, Jianan Guo, Changjun Zhang, Yuanyuan Xie
Summary: Alzheimer's disease (AD) is a progressive brain disease that results in memory loss and cognitive impairment, leading to death. This review focuses on the development of dual inhibitors that target both acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B), which are considered to contribute to AD pathologies. The inhibitors are classified into six groups based on their parent structures, and their design strategies, structure-activity relationships (SARs), and molecular docking studies with AChE and MAO-B are analyzed. The review provides valuable insights for the future development of AChE and MAO-B dual inhibitors, while also addressing the challenges and providing corresponding solutions.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Thierno Moussa Ndongo, Marieta L. C. Passos, Fernando Duraes, Diana I. S. P. Resende, Madalena Pinto, Emilia Sousa, Maria Lucia M. F. S. Saraiva
Summary: A miniaturized microsequential injection/lab-on-valve (mu SIA-LOV) system has been developed as a useful alternative for inhibitory studies on acetylcholinesterase, showing potential inhibitory effects higher than clinical agents at lower costs and reagent consumption. The system is robust, rapid, reliable, and easy to use.
ARCHIV DER PHARMAZIE
(2021)
Article
Biochemistry & Molecular Biology
K. Dileep, Naoki Sakai, Kentaro Ihara, Miyuki Kato-Murayama, Akiko Nakata, Akihiro Ito, D. M. Sivaraman, Jay W. Shin, Minoru Yoshida, Mikako Shirouzu, Kam Y. J. Zhang
Summary: Alzheimer's disease is a major public health concern with limited therapeutic options. Inhibiting sQC to prevent the formation of neurotoxic pGlu-Aβ offers a promising disease-modifying therapy for AD. A novel sQC inhibitor, Cpd-41, was identified with unique binding mode and moderate toxicity, making it a potential candidate for designing high affinity sQC inhibitors.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2021)
Article
Neurosciences
Leah K. Cuddy, Alia O. Alia, Miranda A. Salvo, Sidhanth Chandra, Tom N. Grammatopoulos, Craig J. Justman, Peter T. Lansbury, Joseph R. Mazzulli, Robert Vassar
Summary: New data suggest that LNK-754 promoted axonal trafficking and function of endolysosomal compartments, reducing amyloid plaque deposition in 5XFAD mice. FTIs may have important therapeutic implications for treating AD.
MOLECULAR NEURODEGENERATION
(2022)
Review
Biochemistry & Molecular Biology
Beatrice Balboni, Mirco Masi, Walter Rocchia, Stefania Girotto, Andrea Cavalli
Summary: Most kinase inhibitors target ATP-binding sites, resulting in promiscuity and potential off-target effects. Allostery provides an alternative approach to achieve selectivity, but its exploitation is challenging due to diverse mechanisms and long-range conformational effects. GSK-3 beta, a critical target involved in multiple pathologies, shares a highly homologous ATP-binding site with other kinases. Allostery offers the potential for selective and moderate inhibition, which is desirable for GSK-3 beta. However, the development of allosteric inhibitors for GSK-3 beta has been limited, with only one reaching clinical trials, and there are no X-ray structures of GSK-3 beta with allosteric inhibitors in the PDB data bank.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Honghua Zhang, Yuying Wang, Yuqing Wang, Xuelin Li, Shuzhi Wang, Zhen Wang
Summary: Alzheimer's disease is the fourth leading cause of death among the elderly worldwide, posing enormous challenges to society. Developing multi-target directed ligands has become a major strategy in combating AD due to its complex pathogenesis. Carbamate moiety, which shares structural similarity to the neurotransmitter acetylcholine, has received significant attention in the discovery of multifunctional cholinesterase inhibitors. Preclinical studies have shown that carbamate-based cholinesterase inhibitors can effectively increase the level of acetylcholine and improve cognitive impairments and behavioral deficits, providing a promising approach for AD treatment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Marwa Malhis, Senthilvelrajan Kaniyappan, Isabelle Aillaud, Ram Reddy Chandupatla, Lisa Marie Ramirez, Markus Zweckstetter, Anselm H. C. Horn, Eckhard Mandelkow, Heinrich Sticht, Susanne Aileen Funke
Summary: The study identified D-enantiomeric peptides MMD3 and its retro-inverso form, MMD3rev, as inhibitors of fibrillization of the PHF6* peptide, the repeat domain of Tau and full-length Tau in in vitro studies. The peptides prevented the formation of beta-sheet-rich fibrils by diverting Tau into large amorphous aggregates, suggesting their potential as therapeutic and diagnostic molecules in Alzheimer's disease research.
