Anti-Parkinsonian L-Dopa can also act as anti-systemic amyloidosis—A mechanistic exploration

Nusrat, Saima; Zaidi, Nida; Siddiqi, Mohammad Khursheed; Zaman, Masihuz; Siddique, Ibrar; Ajmal, Mohammad; Khan, Rizwan Hasan

doi:10.1016/j.ijbiomac.2017.03.028

Cited by 17 publications

(10 citation statements)

References 58 publications

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“…It effectively inhibited fibril formation or could disaggregate existing fibrillar aggregates of the amyloid polypeptide and α-synuclein in vitro . Levodopa has further been shown to inhibit and depolymerize human lysozyme amyloid fibrils in systemic amyloidosis by potentiating hydrophobic interactions and enabling hydrogen bond formation with the amino acid entities located in the amyloid prone area of the human lysozyme …”

Section: Resultsmentioning

confidence: 99%

Anti-Amyloidogenic and Fibril-Disaggregating Potency of the Levodopa-Functionalized Gold Nanoroses as Exemplified in a Diphenylalanine-Based Amyloid Model

et al. 2022

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The phenomenon of proteins/peptide assembly into amyloid fibrils is associated with various neurodegenerative and agerelated human disorders. Inhibition of the aggregation behavior of amyloidogenic peptides/proteins or disruption of the pre-formed aggregates is a viable therapeutic option to control the progression of various protein aggregation-related disorders such as Alzheimer's disease (AD). In the current work, we investigated both the amyloid inhibition and disaggregation proclivity of levodopa-functionalized gold nanoroses (GNRs) against various peptide-based amyloid models, including the amyloid beta peptide [Aβ (1−42) and Aβ (1−40)] and the dipeptide phenylalanine−phenylalanine (FF). Our results depicted the antiaggregation behavior of the GNR toward FF and both forms of Aβderived fibrils. The peptides demonstrated a variation in their fiber-like morphology and a decline in thioflavin T fluorescence after being coincubated with the GNR. We further demonstrated the neuroprotective effects of the GNR in neuroblastoma cells against FF and Aβ (1−42) fiber-induced toxicity, exemplified both in terms of regaining cellular viability and reducing production of reactive oxygen species. Overall, these findings support the potency of the GNR as a promising platform for combating AD.

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Section: Resultsmentioning

confidence: 99%

Anti-Amyloidogenic and Fibril-Disaggregating Potency of the Levodopa-Functionalized Gold Nanoroses as Exemplified in a Diphenylalanine-Based Amyloid Model

et al. 2022

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“…It is rather remarkable that the risk of AD could be significantly decreased by long-term dietary intake of flavonoids . (ii) Drugs that are approved by the Food and Drug Administration (FDA), such as promethazine, levodopa, diuretics, and some nonsteroidal anti-inflammatory drugs, − as well as some small molecules, for instance, indole derivatives and acridine derivatives, are known as inhibitors of amyloid fibrillation and can reduce the cytotoxicity of protein amyloid fibers. , (iii) Novel small-molecule compounds, such as water-soluble curcumin derivatives, have been widely investigated for their inhibitory effects on amyloid fibers. , Interestingly, some vitamins also show significant inhibitory activity on the formation of amyloid fibers. , …”

Section: Introductionmentioning

confidence: 99%

“…Human lysozyme (HL) is a small globular protein, which adopts different structural changes under specific conditions . HL consists of 130 amino acid residues, of which Trp 64 and Trp 109 are verified as the most dominant fluorophores in the substrate-binding region for lytic activity . The experimental findings suggest that HL has the potential to form amyloid fibers in vitro , and its mechanism of fibril formation has been proposed .…”

Section: Introductionmentioning

confidence: 99%

“…22 HL consists of 130 amino acid residues, of which Trp 64 and Trp 109 are verified as the most dominant fluorophores in the substrate-binding region for lytic activity. 12 The experimental findings suggest that HL has the potential to form amyloid fibers in vitro 13,14 and its mechanism of fibril formation has been proposed. 23 HL has become an important model protein in the study of amyloid formation because of its amyloid formation conditions, conformational changes, and cytotoxicity.…”

Section: ■ Introductionmentioning

confidence: 99%

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Attenuation of Human Lysozyme Amyloid Fibrillation by ACE Inhibitor Captopril: A Combined Spectroscopy, Microscopy, Cytotoxicity, and Docking Study

et al. 2021

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Misfolding proteins could form oligomers or amyloid fibers, which can cause a variety of amyloid-associated diseases. Thus, the inhibition of protein misfolding and fibrillation is a promising way to prevent and treat these diseases. Captopril (CAP) is an angiotensin-converting enzyme inhibitor (ACEI) that is widely used to treat diseases such as hypertension and heart failure. In this study, we found that CAP inhibits human lysozyme (HL) fibrillation through the combination techniques of biophysics and biochemistry. The data obtained by thioflavin-T (ThT) and Congo red (CR) assays showed that CAP hindered the aggregation of HL amyloid fibrils by reducing the β-sheet structure of HL amyloid, with an IC50 value of 34.75 ± 1.23 μM. Meanwhile, the particle size of HL amyloid decreased sharply in a concentration-dependent approach after CAP treatment. According to the visualization of atomic force microscopy (AFM) and transmission electron microscopy (TEM), we verified that in the presence of CAP, the needle-like fibers of HL amyloid were significantly reduced. In addition, CAP incubation dramatically improved the cell survival rate exposed to HL fibers. Our studies also revealed that CAP could form hydrogen bonds with amino acid residues of Glu 35 and Ala 108 in the binding pocket of HL, which help in maintaining the α-helical structure of HL and then prevent the formation of amyloid fibrillation. It can be concluded that CAP has antiamyloidogenic activity and a protective effect on HL amyloid cytotoxicity.

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“…Several potent compounds have been reported to have the ability of amyloid inhibition (Awasthi et al, 2016 ; Mohamed et al, 2016 ; Nusrat et al, 2016 ), which include such as polyphenols, nanoparticles, flavonoids, vitamins, various drugs (Lee et al, 2012 ; Alam P. et al, 2016 ; Nedumpully-Govindan et al, 2016 ; Nusrat et al, 2017 ; Usmani et al, 2017 ). Certainly, detecting and uncovering the mechanisms of amyloid aggregation with an insight at molecular level are of diagnostic significance and have therapeutic consequences.…”

Section: Introductionmentioning

confidence: 99%

Elucidating the Inhibitory Potential of Designed Peptides Against Amyloid Fibrillation and Amyloid Associated Cytotoxicity

et al. 2018

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Inhibition of fibrillation process and disaggregation of mature fibrils using small peptide are the promising remedial strategies to combat neurodegenerative diseases. However, designing peptide-based drugs to target β-sheet-rich amyloid has been a major challenge. The current work describes, for the first time, the amyloid inhibitory potential of the two short peptides (selected on the basis of predisposition of their amino acid residues toward β-sheet formation) using combination of biophysical, imaging methods, and docking approaches. Results showed that peptides employed different mechanisms to inhibit the amyloid fibrillation. Furthermore, they were also effective in blocking the amyloid fibrillation pathway. In contrary to the insulin fibrillar mesh, significantly less fibrillar species appeared in the presence of peptides, as confirmed by transmission electron microscopy. Circular dichroism analysis indicated that although peptides did not stabilize the native state of insulin, they inhibited amyloid aggregation by reducing the formation of β-sheet rich structures. Hemolytic assay revealed the non-hemolytic nature of the species formed when insulin was co-incubated with the peptides. Therefore, despite the inherent potential to form β-sheet structure, these peptides inhibited the amyloid formation and potentially can be used as therapeutics for the treatment of amyloid-related diseases.

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Anti-Parkinsonian L-Dopa can also act as anti-systemic amyloidosis—A mechanistic exploration

Cited by 17 publications

References 58 publications

Anti-Amyloidogenic and Fibril-Disaggregating Potency of the Levodopa-Functionalized Gold Nanoroses as Exemplified in a Diphenylalanine-Based Amyloid Model

Anti-Amyloidogenic and Fibril-Disaggregating Potency of the Levodopa-Functionalized Gold Nanoroses as Exemplified in a Diphenylalanine-Based Amyloid Model

Attenuation of Human Lysozyme Amyloid Fibrillation by ACE Inhibitor Captopril: A Combined Spectroscopy, Microscopy, Cytotoxicity, and Docking Study

Elucidating the Inhibitory Potential of Designed Peptides Against Amyloid Fibrillation and Amyloid Associated Cytotoxicity

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