Thiacalixarene Carboxylic Acid Derivatives as Inhibitors of Lysozyme Fibrillation

Author:

Nazarova Anastasia1ORCID,Shiabiev Igor1ORCID,Shibaeva Ksenia1,Mostovaya Olga1,Mukhametzyanov Timur1ORCID,Khannanov Arthur1ORCID,Evtugyn Vladimir2,Zelenikhin Pavel3ORCID,Shi Xiangyang45ORCID,Shen Mingwu4ORCID,Padnya Pavel1ORCID,Stoikov Ivan1ORCID

Affiliation:

1. A. M. Butlerov Chemistry Institute, Kazan Federal University, 18 Kremlyovskaya Str., 420008 Kazan, Russia

2. Interdisciplinary Center of Analytical Microscopy, Kazan Federal University, 18 Kremlyovskaya Str., 420008 Kazan, Russia

3. Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlyovskaya Str., 420008 Kazan, Russia

4. State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China

5. CQM—Centro de Química da Madeira, Universidade da Madeira, Campus Universitário da Penteada, 9020-105 Funchal, Portugal

Abstract

Amyloid fibroproliferation leads to organ damage and is associated with a number of neurodegenerative diseases affecting populations worldwide. There are several ways to protect against fibril formation, including inhibition. A variety of organic compounds based on molecular recognition of amino acids within the protein have been proposed for the design of such inhibitors. However, the role of macrocyclic compounds, i.e., thiacalix[4]arenes, in inhibiting fibrillation is still almost unknown. In the present work, the use of water-soluble thiacalix[4]arene derivatives for the inhibition of hen egg-white lysozyme (HEWL) amyloid fibrillation is proposed for the first time. The binding of HEWL by the synthesized thiacalix[4]arenes (logKa = 5.05–5.13, 1:1 stoichiometry) leads to the formation of stable supramolecular systems capable of stabilizing the protein structure and protecting against fibrillation by 29–45%. The macrocycle conformation has little effect on protein binding strength, and the native HEWL secondary structure does not change via interaction. The synthesized compounds are non-toxic to the A549 cell line in the range of 0.5–250 µg/mL. The results obtained may be useful for further investigation of the anti-amyloidogenic role of thiacalix[4]arenes, and also open up future prospects for the creation of new ways to prevent neurodegenerative diseases.

Funder

Russian Science Foundation

Publisher

MDPI AG

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