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Current Pharmaceutical Biotechnology

Author(s): Shivani Kumar, Manoj Kumar, Yogesh K. Tyagi* and Suresh Kumar*

DOI: 10.2174/1389201021666200915112849

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Inhibition of Amyloid Fibrillation of HEWL by 4-Methylcoumarin and 4-Methylthiocoumarin Derivatives

Page: [232 - 244] Pages: 13

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Abstract

Background: Several human diseases like Parkinson’s, Alzheimer’s disease, and systemic amyloidosis are associated with the misfolding and aggregation of protein molecules.

Objective: The present study demonstrated the comparison of 4-methyl coumarin and 4-methylthiocoumarin derivative for their anti-amyloidogenic and disaggregation activities. The hen egg-white lysozyme is used as a model system to study protein aggregation and disaggregation under in vitro conditions.

Methods: Techniques used in the study were Thioflavin T fluorescence assay, intrinsic fluorescence assay, circular dichroism, transmission electron microscopy, and molecular dynamics.

Results: Fifteen compounds were screened for their anti-amyloidogenic and disaggregation potential. Six compounds significantly inhibited the fibril formation, whereas ten compounds showed disaggregation property of pre-formed fibrils. Under in vitro conditions, the compound C3 and C7 showed significant inhibition of fibril formation in a concentration-dependent manner as compared to control. C3 and C7 demonstrated 93% and 76% inhibition of fibril formation, respectively. Furthermore, C3 and C7 exhibited 83% and 76% disaggregation activity, respectively, of pre-formed HEWL fibrils at their highest concentration. These anti-amyloidogenic and disaggregation potential of C3 and C7 were validated by intrinsic fluorescence, CD, molecular dynamics, and TEM study.

Discussion: 4-methylthiocoumarins derivatives have shown better anti-amyloidogenic activity as compared to 4-methylcoumarin derivatives for both amyloid formation as well as disaggregation of preformed amyloid fibrils. Structurally, the derivatives of 4-methylthiocoumarins (C3 and C7) contain thio group on 2nd position that might be responsible for anti-amyloidogenic activity as compared to 4- methylcoumarin derivatives (C2 and C4).

Conclusion: C3 and C7 are novel 4-methylthiocoumarin derivatives that can be used as a lead for alleviation and symptoms associated with protein aggregation disorders.

Keywords: HEWL, 4-methylcoumarin, 4-methylthiocoumarin, anti-amyloidogenic activity, amyloidosis, amyloid fibril.

Graphical Abstract

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