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Basified Human Lysozyme: A Potent Inhibitor Against Amyloid β-Protein Fibrillogenesis

Basified Human Lysozyme: A Potent Inhibitor Against Amyloid β-Protein Fibrillogenesis

Xi Li, Baolong Xie, Yan Sun

Langmuir. 2018 Dec 18;34(50):15569-15577.

PMID: 30407837

Abstract:

The aggregation of amyloid β-proteins (Aβ) has been recognized as a key process in the pathogenesis of Alzheimer's disease (AD), so inhibiting Aβ aggregation is an important strategy to prevent the onset and treatment of AD. Our recent work indicated that decreasing the positive charges (or introducing negative charges) on human lysozyme (hLys) was unfavorable in keeping the inhibiting capability of hLys on Aβ aggregation. Therefore, we have herein proposed to basify hLys by conversion of the carboxyl groups into amino groups by modification with ethylene diamine. Basified hLys (Lys-B) preparations of three modification degrees (MDs), denoted as hLys-B1 (MD, 1.5), hLys-B2 (MD, 3.3), and hLys-B3 (MD, 4.4), were synthesized for modulating Aβ fibrillogenesis. The hLys-B preparations kept the stability and biocompatibility as native hLys did, whereas the inhibitory potency of hLys-B on Aβ fibrillogenesis increased with increasing MD. Cytotoxicity analysis showed that cell viability with 2.5 μM hLys-B3 increased from 62.5% (with 25 μM Aβ only) to 76.1%, similar to the case with 12.5 μM hLys (75.5%); cell viability with 6.25 μM hLys-B3 increased to 82.0%, similar to the case with 25 μM hLys (80.9%). The results indicate about four- to fivefold increase in the inhibition efficiency of hLys by the amino modification. Mechanistic analysis suggests that such a superior inhibitory capability of hLys-B was attributed to its more widely distributed positive charges, which promoted broad electrostatic interactions between Aβ and hLys-B. Thus, hLys-B suppressed the conformational transition of Aβ to β-sheet structures at low concentrations (e.g., 2.5 μM hLys-B3), leading to changes in the aggregation pathway and the formation of Aβ species with less cytotoxicity. The findings provided new insights into the development of more potent protein-based inhibitors against Aβ fibrillogenesis.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP12671191	Lysozyme human		12671-19-1	Price

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