An antioxidant boehmite amino-nanozyme able to disaggregate Huntington's inclusion bodies

Martínez‐Camarena, Álvaro; Merino, Marián; Sanchez‐Sanchez, Ana; Blasco, Salvador; Llinares, José M.; Mullor, José Luis; Garcı́a-España, Enrique

doi:10.1039/d2cc01257j

Cited by 14 publications

(10 citation statements)

References 32 publications

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“…19−22 The design of a ligand that strongly binds misregulated copper ions with concomitant SOD-like reactivity as a complex offers an attractive opportunity to serve as a bimodal therapeutic antioxidant, but species with these characteristics have remained elusive to date. 23,24 Nonheme ligand scaffolds were designed to overcome some of the deficiencies found with porphyrins as Cu-SOD mimics. 22,24−26 Martinez-Camarena et al investigated the SOD reactivity with the Cu(II) pyridinophane complex [CuPyN 3 ] 2+ (IC 50 = 2.1 μM, k cat = 1.7 × 10 6 M −1 s −1 ), showing remarkable catalytic activity in comparison with other mimics in the literature.…”

Section: •−mentioning

confidence: 99%

“…Copper porphyrin complexes have also been shown to provide SOD-like reactivity. ,, However, the low metal-to-ligand (ML) binding stabilities (log β ML ) of Cu(II) with porphyrins discouraged further studies of this scaffold due to the observed competition between SOD activity and ROS-generating Haber–Weiss-like chemistry. Therefore, the role of misregulated copper in ROS-generating reactions and its apparent involvement in diseases related to oxidative stress, such as Huntington’s disease, have encouraged the study of copper-based antioxidants. − The design of a ligand that strongly binds misregulated copper ions with concomitant SOD-like reactivity as a complex offers an attractive opportunity to serve as a bimodal therapeutic antioxidant, but species with these characteristics have remained elusive to date. , …”

Section: Introductionmentioning

confidence: 99%

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Increased Efficiency of a Functional SOD Mimic Achieved with Pyridine Modification on a Pyclen-Based Copper(II) Complex

et al. 2023

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A series of Cu(II) complexes with the formula [Cu R PyN 3 ] 2+ varying in substitution on the pyridine ring were investigated as superoxide dismutase (SOD) mimics to identify the most efficient reaction rates produced by a synthetic, water-soluble copper-based SOD mimic reported to date. The resulting Cu(II) complexes were characterized by X-ray diffraction analysis, UV–visible spectroscopy, cyclic voltammetry, and metal-binding (log β) affinities. Unique to this approach, the modifications to the pyridine ring of the PyN 3 parent system tune the redox potential while exhibiting high binding stabilities without changing the coordination environment of the metal complex within the PyN 3 family of ligands. We were able to adjust in parallel the binding stability and the SOD activity without compromising on either through simple modification of the pyridine ring on the ligand system. This goldilocks effect of high metal stabilities and high SOD activity reveals the potential of this system to be explored in therapeutics. These results serve as a guide for factors that can be modified in metal complexes using pyridine substitutions for PyN 3 , which can be incorporated into a range of applications moving forward.

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Section: •−mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increased Efficiency of a Functional SOD Mimic Achieved with Pyridine Modification on a Pyclen-Based Copper(II) Complex

et al. 2023

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“…After incubation with the compound, the cells were processed for mHtt quantification using immunofluorescence (under an In-Cell Analyzer automatic fluorescence microscope), and in parallel, the cells were lysed, and the total mHtt was analysed by Western blot. In the immunofluorescence assay, quantification was performed with the In-cell Analyzer software, and the cells were also treated with L1 (3,6,9-triaza-1(2,6)-pyridinecyclodecaphane-14-carboxylic acid), a compound that forms Cu 2+ complexes and mimics SOD activity such as 4QMn [ 23 ]. After a 24 h treatment with 4QMn, we observed that the percentage of positive cells with mHtt was significantly decreased by 40.4 ± 8.6%, compared to non-treated cells.…”

Section: Resultsmentioning

confidence: 99%

Mn(II) Quinoline Complex (4QMn) Restores Proteostasis and Reduces Toxicity in Experimental Models of Huntington’s Disease

Merino¹,

Sequedo

Sanchez‐Sanchez³

et al. 2022

IJMS

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Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder, of the so-called minority diseases, due to its low prevalence. It is caused by an abnormally long track of glutamines (polyQs) in mutant huntingtin (mHtt), which makes the protein toxic and prone to aggregation. Many pathways of clearance of badly-folded proteins are disrupted in neurons of patients with HD. In this work, we show that one Mn(II) quinone complex (4QMn), designed to work as an artificial superoxide dismutase, is able to activate both the ubiquitin-proteasome system and the autophagy pathway in vitro and in vivo models of HD. Activation of these pathways degrades mHtt and other protein-containing polyQs, which restores proteostasis in these models. Hence, we propose 4QMn as a potential drug to develop a therapy to treat HD.

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“…Nanozymes are enzymatically active nanomaterials that share some similarities with natural enzymes in terms of overall size, shape, and surface charge, but are more resistant to harsh environments and can adapt to wide pH range and temperature variations [42]. A novel amino-nanozyme based on boehmite NPs functionalized with tetraazapyridinophane could cross the BBB, scavenge mitochondrial reactive oxygen species, and disaggregate mutant Huntington deposits [43].…”

Section: Inorganic-based Npsmentioning

confidence: 99%

Nanoparticle-Based Drug Delivery Systems: An Inspiring Therapeutic Strategy for Neurodegenerative Diseases

Duan

et al. 2023

Polymers

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Neurodegenerative diseases are common, incurable neurological disorders with high prevalence, and lead to memory, movement, language, and intelligence impairments, threatening the lives and health of patients worldwide. The blood–brain barrier (BBB), a physiological barrier between the central nervous system and peripheral blood circulation, plays an important role in maintaining the homeostasis of the intracerebral environment by strictly regulating the transport of substances between the blood and brain. Therefore, it is difficult for therapeutic drugs to penetrate the BBB and reach the brain, and this affects their efficacy. Nanoparticles (NPs) can be used as drug transport carriers and are also known as nanoparticle-based drug delivery systems (NDDSs). These systems not only increase the stability of drugs but also facilitate the crossing of drugs through the BBB and improve their efficacy. In this article, we provided an overview of the types and administration routes of NPs, highlighted the preclinical and clinical studies of NDDSs in neurodegenerative diseases, and summarized the combined therapeutic strategies in the management of neurodegenerative diseases. Finally, the prospects and challenges of NDDSs in recent basic and clinical research were also discussed. Above all, NDDSs provide an inspiring therapeutic strategy for the treatment of neurodegenerative diseases.

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An antioxidant boehmite amino-nanozyme able to disaggregate Huntington's inclusion bodies

Abstract: A novel amino-nanozyme, based on boehmite nanoparticles (BNPs) functionalised with a tetra-azapyridinophane (L1), has been designed to undermine some of the key issues underlying Huntington disease. L1 forms Cu2+ complexes...

Cited by 14 publications

References 32 publications

Increased Efficiency of a Functional SOD Mimic Achieved with Pyridine Modification on a Pyclen-Based Copper(II) Complex

Increased Efficiency of a Functional SOD Mimic Achieved with Pyridine Modification on a Pyclen-Based Copper(II) Complex

Mn(II) Quinoline Complex (4QMn) Restores Proteostasis and Reduces Toxicity in Experimental Models of Huntington’s Disease

Nanoparticle-Based Drug Delivery Systems: An Inspiring Therapeutic Strategy for Neurodegenerative Diseases

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