Metal Binding by GMP-1 and Its Pyrimido [1, 2]benzimidazole Analogs Confirms Protection Against Amyloid-β Associated Neurotoxicity.
| Autor: | Kumar, Rajnish, Pavlov, Pavel F., Winblad, Bengt |
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| Předmět: |
BENZIMIDAZOLES
AMYLOID NEUROTOXICOLOGY ALZHEIMER'S disease TREATMENT effectiveness METALS APOLIPOPROTEIN E4 DRUG development CEREBRAL amyloid angiopathy ZINC metabolism COPPER metabolism NEUROLOGICAL disorder prevention QUINOLINE RESEARCH NEUROLOGICAL disorders HETEROCYCLIC compounds RESEARCH methodology CHELATING agents EVALUATION research MEDICAL cooperation OXIDATIVE stress COMPARATIVE studies NEUROPROTECTIVE agents CELL lines REACTIVE oxygen species PEPTIDES LIGANDS (Biochemistry) CELL death CHEMICAL inhibitors |
| Zdroj: | Journal of Alzheimer's Disease; 2020, Vol. 73 Issue 2, p695-705, 11p |
| Abstrakt: | Alzheimer's disease (AD) represents a major public health threat and, unfortunately, available therapeutics provide only temporary symptomatic relief. AD is a complex multifactorial disease and failure of single target therapeutics targeting amyloid-β (Aβ) in recent clinical trials suggests that future AD drug development should be focused on simultaneous targeting of several pathological hallmarks of the disease. Recently, we have shown that GMP-1, a 2-(methoxymethyl)pyrimido [1, 2-a] benzimidazol-4-ol, protects mitochondrial function in drosophila and mice models of AD, and improved memory and behavior indicating neuroprotective effect of GMP-1 treatment. Here, we have found that GMP-1 specifically binds to copper and zinc, metals that are dysregulated in AD brain. Addition of GMP-1 does not inhibit metal-dependent enzymatic reactions. Also, binding of Zn(II) and Cu(II) by GMP-1 is weaker than the 8-hydroxyquinoline scaffold compound clioquinol previously tested in AD clinical trials. However, GMP-1 affects Cu(II)-dependent Aβ fibrillization as well as oxidative damage and viability of SH-SY5Y cells upon addition of Cu(II) and Aβ. Our data provide new insight on GMP-1 as a Zn(II) and Cu(II) specific metal chelator of moderate affinity that can be responsible for some of its neuroprotective effects observed in AD animal models. [ABSTRACT FROM AUTHOR] |
| Databáze: | Complementary Index |
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