Discovery of highly potent human glutaminyl cyclase (QC) inhibitors as anti-Alzheimer's agents by the combination of pharmacophore-based and structure-based design

Mạnh, Nguyễn Văn; Hoang, Van-Hai; Ngo, Van T.H.; Ann, Jihyae; Jang, Tae Ho; Ha, Jung-Hye; Song, Jae Young; Ha, Hee-Jin; Kim, Hee; Kim, Young‐Ho; Lee, Jiyoun; Lee, Jeeyeon

doi:10.1016/j.ejmech.2021.113819

Cited by 9 publications

(7 citation statements)

References 62 publications

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“…As such, to improve AD and aging brain lesions, Pun may influence Aβ in the circulatory system by activating ALB . A cohort study demonstrated that brain AKT phosphorylation (pT 308 AKT1/total AKT1) is a key node of growth factors signal transduction, for example, insulin, which is associated with AD neuropathology and cognitive dysfunction . More evidence has shown a role for the tyrosine phosphotransferase Fyn of SRC family nonreceptor kinases in the pathophysiological changes of AD .…”

Section: Discussionmentioning

confidence: 99%

“…7 A cohort study demonstrated that brain AKT phosphorylation (pT 308 AKT1/total AKT1) is a key node of growth factors signal transduction, for example, insulin, which is associated with AD neuropathology and cognitive dysfunction. 8 More evidence has shown a role for the tyrosine phosphotransferase Fyn of SRC family nonreceptor kinases in the pathophysiological changes of AD. 9 The soluble polymer binds with high affinity to the cellular prion protein on the surface of neuronal cells, triggering a pathological cascade on the nonreceptor tyrosine kinase Fyn.…”

Section: Discussionmentioning

confidence: 99%

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Analysis of the Molecular Mechanism of Punicalagin in the Treatment of Alzheimer’s Disease by Computer-Aided Drug Research Technology

Shu-yun

et al. 2022

ACS Omega

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The objective of this work is to explore the effect and potential mechanism of Punicalagin (Pun) in managing Alzheimer’s disease (AD) based on computer-aided drug technology. The following methods were used: the intersection genes of Pun and AD were retrieved from the database and subjected to PPI analysis, GO, and KEGG enrichment analyses. Preliminary verification was performed by molecular docking, molecular dynamics (MD) simulation, and combined free energy calculation. The motor coordination and balance ability, anxiety degree, spatial learning, and memory ability of mice were measured by a rotating rod fatigue instrument, elevated cross maze, and Y maze, respectively. The amyloid β protein (Aβ) in the hippocampus was examined by immunohistochemistry, and the phosphorylation of serine at position 404 of the tau protein (Tau-pS404) was examined by western blot in the mouse brain. The PPI network of Pun showed that the intersection genes were closely related and enriched in muscle cell proliferation and the response to lipopolysaccharide. Results of molecular docking, MD simulations, and MM-GBSA demonstrated that Pun was closely bound to the target protein. Pun could improve the cognitive function of AD mice, as well as reduce Aβ1‑42 deposition and Tau phosphorylation in the brain (P < 0.05, P < 0.01). It can be concluded that Pun holds great promise in improving the cognitive function of AD mice. Mechanistically, Pun potentially acts on ALB, AKT1, SRC, EGFR, CASP3, and IGF-1 targets and mediates proteoglycan, lipid, and atherosclerosis in cancer, so as to reduce the accumulation of neurotoxic proteins in the brain.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Analysis of the Molecular Mechanism of Punicalagin in the Treatment of Alzheimer’s Disease by Computer-Aided Drug Research Technology

Shu-yun

et al. 2022

ACS Omega

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“…AbpE has been treated as a drug target in AD, and drugs such as donanemab (a humanized IgG1 monoclonal antibody to the pyroglutamylated form of Ab) are in phase II clinical trials [122][123][124][125][126]. Many Ab peptides possess a pGlu residue catalyzed by QC [127], and the pyroglutamylation of Ab is highly abundant in the brains of AD patients, protecting it from protease degradation and making it more hydrophobic and prone to aggregation, which might increase its neurotoxicity [24,101,128,129].…”

Section: Qc/isoqc In Neuron Diseasesmentioning

confidence: 99%

“…In addition to all the above inhibitors, new heterocyclic and peptidomimetic derivatives to inhibit QC and isoQC are still under investigation. In Dec. 2021, the cyclopentylmethyl derivative (214) exhibited the most potent in vitro activity (IC50 = 0.1 nM), which is 290-fold higher than that of PQ912, and benzimidazole (227) showed the most promising in vivo efficacy [123].…”

Section: Pq912mentioning

confidence: 99%

Functions of glutaminyl cyclase and its isoform in diseases

Liu

Wang²

2023

Vis Cancer Med

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Glutaminyl cyclase (QC; isoform: isoQC) is a zinc-dependent enzyme that catalyzes the intramolecular cyclization of N-terminal glutamine and glutamic acid residues into a pyroglutamate residue (pGlu). This conversion is a type of posttranslational modification called pyroglutamylation. The expression of QC/isoQC is regulated by epigenetics, cell homeostasis, and its substrates. Pyroglutamylation is an important maturation process during the synthesis and secretion of hormones, functioning in different diseases, such as Alzheimer’s disease, tumors, and other kinds of chronic diseases mediated by inflammation. IsoQC has been identified as a key regulator of the CD47-SIRPα checkpoint and is critical for the pyroglutamylation of CD47 at its SIRPα binding site, thus helping cancer cells evade immune surveillance. Inhibition of isoQC blocks the interaction between CD47 and SIRPα, leading to constrained tumor growth, indicating that isoQC is a novel target for immunotherapy. Targeting isoQC overcomes the side effects of targeting CD47 because isoQC is Golgi resident and is not expressed on erythrocytes. Small molecules and antibodies have been developed to target isoQC, and some of them have been tested in preclinical or clinical studies. Here, we briefly review the discovery history of QC/isoQC and then discuss its regulation and function in different diseases, emphasizing the unique role of isoQC in immunotherapy. Finally, we summarize the development of inhibitors and their progress in clinical trials with the hope of providing useful insights for future investigation of QC/isoQC and targeting it in various diseases.

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“…It substantially decreases quality of life and increases morbidity. [ 1‐2 ] As reported in World Alzheimer Report 2020, there are currently estimated over 55 million people worldwide living with dementia. The number of people affected is set to rise to 139 million by 2050, with the greatest increases in low and middle income countries.…”

Section: Background and Originality Contentmentioning

confidence: 99%

Discovery of Tryptophan‐tetrahydroisoquinoline Derivatives as Multifunctional Agents for Treatment of Alzheimer's Disease

et al. 2022

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The cholinesterases are essential targets implicated in the pathogenesis of Alzheimer's disease (AD). We have identified tryptophan-tetrahydroisoquinoline derivatives as selective micro-nanomolar butyrylcholinesterase (BChE) inhibitors. Molecular docking was applied for the rational design and binding mode analysis. They were defined according to their target inhibitory activity, low cytotoxicity, predicted permeability through the blood-brain barrier (BBB), and in vivo cognitive improvement. Additionally, the preferred compound showed ability to decrease self-induced Aβ 1-42 aggregation and Aβ 1-42 induced SH-SY5Y cell injury. Altogether, these factors indicated their potential as unique lead compounds for AD treatment..

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Discovery of highly potent human glutaminyl cyclase (QC) inhibitors as anti-Alzheimer's agents by the combination of pharmacophore-based and structure-based design

Cited by 9 publications

References 62 publications

Analysis of the Molecular Mechanism of Punicalagin in the Treatment of Alzheimer’s Disease by Computer-Aided Drug Research Technology

Analysis of the Molecular Mechanism of Punicalagin in the Treatment of Alzheimer’s Disease by Computer-Aided Drug Research Technology

Functions of glutaminyl cyclase and its isoform in diseases

Discovery of Tryptophan‐tetrahydroisoquinoline Derivatives as Multifunctional Agents for Treatment of Alzheimer's Disease

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