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

Jin, Li; Liu, Chunhong; Zhang, Ning; Zhang, Ruiyan; Yan, Mingdi; Bhunia, Anirban; Zhang, Qinxiu; Liu, Min; Han, Jun; Siebert, Hans‐Christian

doi:10.1021/acs.biomac.0c01802

Cited by 32 publications

(20 citation statements)

References 68 publications

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“…The extent of protein aggregation after a prolonged incubation period can be understood from Congo red binding assay. The binding of CR to the β-sheet structures of protein fibrils leads to an increased absorption intensity along with a red-shift in peak position when compared with that observed in native protein Figure S6 shows the spectral changes of CR absorption in HEWL protein solutions prepared at different time periods (0 h, 40 h, 60 h) of incubation in the absence and presence of bile acids.…”

Section: Resultsmentioning

confidence: 99%

Mechanistic Insight into the Amyloid Fibrillation Inhibition of Hen Egg White Lysozyme by Three Different Bile Acids

et al. 2023

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Amyloid aggregation of protein is linked to many neurodegenerative diseases. Identification of small molecules capable of targeting amyloidogenic proteins has gained significant importance. Introduction of hydrophobic and hydrogen bonding interactions through site-specific binding of small molecular ligand to protein can effectively modulate the protein aggregation pathway. Here, we investigate the possible roles of three different bile acids, cholic acid (CA), taurocholic acid (TCA), and lithocholic acid (LCA) with varying hydrophobic and hydrogen bonding properties in inhibiting protein fibrillation. Bile acids are an important class of steroid compounds that are synthesized in the liver from cholesterol. Increasing evidence suggests that altered taurine transport, cholesterol metabolism, and bile acid synthesis have strong implications in Alzheimer’s disease. We find that the hydrophilic bile acids, CA and TCA (taurine conjugated form of CA), are substantially more efficient inhibitors of lysozyme fibrillation than the most hydrophobic secondary bile acid LCA. Although LCA binds more strongly with the protein and masks the Trp residues more prominently through hydrophobic interactions, the lesser extent of hydrogen bonding interactions at the active site has made LCA a relatively weaker inhibitor of HEWL aggregation than CA and TCA. The introduction of a greater number of hydrogen bonding channels by CA and TCA with several key amino acid residues which are prone to form oligomers and fibrils has weakened the protein’s internal hydrogen bonding capabilities for undergoing amyloid aggregation.

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Section: Resultsmentioning

confidence: 99%

Mechanistic Insight into the Amyloid Fibrillation Inhibition of Hen Egg White Lysozyme by Three Different Bile Acids

et al. 2023

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“…Human lysozyme (HL) was selected as a protein model to explore the inhibitory effects of catechol-o-methyltransferase inhibitor (Entacapone) and angiotensin-converting enzyme (ACE) inhibitor (Captopril) on amyloid aggregation. 35,36 AFM images showed that the number and length of fibrils decreased significantly when HL was co-incubated (1 : 10) with these drugs. Researchers synthesized a series of tacrine-benzothiazoles heterodimers derivatives through structure-based rational drug design.…”

Section: Topographical Imaging Of Protein-drug Interactionmentioning

confidence: 99%

Novel perspective for protein–drug interaction analysis: atomic force microscope

Wang

2023

Analyst

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“…To date, only two strategies are being used to treat AD patients: acetylcholinesterase inhibitors to maintain the level of acetylcholine in the brain and N -methyl- d -aspartate receptor antagonists to prevent excitotoxicity, but none of them alter the progression of disease . Over several years, other strategies have been studied to reduce or disrupt the Aβ assemblies, including immunotherapeutic vaccines, − antibodies, − peptides, , natural compounds, and repurposing drugs. − Because of the AD drug development failures, new strategies like repurposing of drugs have emerged as a viable strategy with the potential to interfere with the underlying disease mechanisms of AD and slow its progression . Due to rising problem of antibiotic resistance, repurposing of antibiotics for treating other disease seems to be a plausible option.…”

Section: Introductionmentioning

confidence: 99%

Moxifloxacin Disrupts and Attenuates Aβ42 Fibril and Oligomer Formation: Plausibly Repositioning an Antibiotic as Therapeutic against Alzheimer’s Disease

Khan

Nabi

Ajmal

et al. 2022

ACS Chem. Neurosci.

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The aggregation of Aβ42 is established as a key factor in the development of Alzheimer's disease (AD). Consequently, molecules that inhibit aggregation of peptide may lead to therapies to prevent or control AD. Several studies suggest that oligomeric intermediates present during aggregation may be more cytotoxic than fibrils themselves. In this work, we examine the inhibitory activity of an antibiotic MXF on aggregation (fibrils and oligomers) and disaggregation of Aβ42 using various biophysical and microscopic studies. Computational analysis was done to offer mechanistic insight. The amyloid formation of Aβ42 is suppressed by MXF, as demonstrated by the decrease in both the corresponding ThT fluorescence intensity and other biophysical techniques. The lag phase of amyloid formation doubled from 4.53 to 9.66 h in the presence of MXF. The addition of MXF at the completion of the fibrillation reaction, as monitored by ThT, led to a rapid, concentration dependent, exponential decrease in fluorescence signal that was consistent with loss of fibrils. We used TEM to directly demonstrate that MXF caused fibrils to disassemble. Our docking results show that MXF binds to both monomeric and fibrillar forms of Aβ42 with significant affinities. We also observed breaking of fibrils in the presence of MXF through molecular dynamics simulation. These findings suggest that antibiotic MXF could be a promising lead compound with dual role as fibril/ oligomer inhibitor and disaggregase for further development as potential repurposed therapeutic against AD.

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

Cited by 32 publications

References 68 publications

Mechanistic Insight into the Amyloid Fibrillation Inhibition of Hen Egg White Lysozyme by Three Different Bile Acids

Mechanistic Insight into the Amyloid Fibrillation Inhibition of Hen Egg White Lysozyme by Three Different Bile Acids

Novel perspective for protein–drug interaction analysis: atomic force microscope

Moxifloxacin Disrupts and Attenuates Aβ42 Fibril and Oligomer Formation: Plausibly Repositioning an Antibiotic as Therapeutic against Alzheimer’s Disease

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