Issue 17, 2024

Thiolated polyglycerol sulfate as potential mucolytic for muco-obstructive lung diseases

Abstract

Increased disulfide crosslinking of secreted mucins causes elevated viscoelasticity of mucus and is a key determinant of mucus dysfunction in patients with cystic fibrosis (CF) and other muco-obstructive lung diseases. In this study, we describe the synthesis of a novel thiol-containing, sulfated dendritic polyglycerol (dPGS-SH), designed to chemically reduce these abnormal crosslinks, which we demonstrate with mucolytic activity assays in sputum from patients with CF. This mucolytic polymer, which is based on a reportedly anti-inflammatory polysulfate scaffold, additionally carries multiple thiol groups for mucolytic activity and can be produced on a gram-scale. After a physicochemical compound characterization, we compare the mucolytic activity of dPGS-SH to the clinically approved N-acetylcysteine (NAC) using western blot studies and investigate the effect of dPGS-SH on the viscoelastic properties of sputum samples from CF patients by oscillatory rheology. We show that dPGS-SH is more effective than NAC in reducing multimer intensity of the secreted mucins MUC5B and MUC5AC and demonstrate significant mucolytic activity by rheology. In addition, we provide data for dPGS-SH demonstrating a high compound stability, low cytotoxicity, and superior reaction kinetics over NAC at different pH levels. Our data support further development of the novel reducing polymer system dPGS-SH as a potential mucolytic to improve mucus function and clearance in patients with CF as well as other muco-obstructive lung diseases.

Graphical abstract: Thiolated polyglycerol sulfate as potential mucolytic for muco-obstructive lung diseases

Supplementary files

Article information

Article type
Paper
Submitted
14 Mar 2024
Accepted
30 Jun 2024
First published
10 Jul 2024
This article is Open Access
Creative Commons BY license

Biomater. Sci., 2024,12, 4376-4385

Thiolated polyglycerol sulfate as potential mucolytic for muco-obstructive lung diseases

J. Arenhoevel, A. Kuppe, A. Addante, L. Wei, N. Boback, C. Butnarasu, Y. Zhong, C. Wong, S. Y. Graeber, J. Duerr, M. Gradzielski, D. Lauster, M. A. Mall and R. Haag, Biomater. Sci., 2024, 12, 4376 DOI: 10.1039/D4BM00381K

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