Much-obstructive respiratory illnesses, such as chronic obstructive lung disease, asthma, and cystic fibrosis, have thick, sticky mucus as a pathophysiologic and clinical component (CF). Mucins, the most abundant biopolymer in mucus, create intricate polymeric networks via covalent disulfide bonds, which control the mucus gel’s viscoelastic properties. Inhaled N-acetylcysteine (NAC) has been utilized as a mucolytic to break down mucin disulfide bonds for decades, with little to no therapeutic benefit. Identification of NAC deficiencies and the creation of drugs to counteract them are required to improve mucolytic therapy. Determine NAC’s pharmacological limitations and test P3001, a new mucin-reducing drug, in preclinical conditions.
In vitro and in vivo models and patient sputa, the researchers performed biochemical (e.g., Western blotting, mass spectrometry) and biophysical (e.g., microrheology/microrheology) spinnability, mucus velocity assessments) assays to test drug efficacy and toxicity. In vitro, dithiothreitol and P3001 were compared to NAC and found to have superior reducing actions. P3001 reduced pulmonary mucus load in βENaC-overexpressing mice in vivo, whereas NAC had no effect (n=6–24 mice per group). Aerosolized NAC was promptly removed from the lungs in NAC-treated CF participants (n=5) and did not affect sputum biophysical characteristics. P3001, on the other hand, functioned faster and at lower doses than NAC, and it outperformed DNase in CF sputum ex vivo. These findings show that using P3001 class mucolytic drugs to reduce the viscoelasticity of airway mucus is a viable therapeutic target.
Reference:www.atsjournals.org/doi/full/10.1164/rccm.201802-0245OC
