ABSTRACT
SARS-CoV-2 S protein-mediated fusion is thought to involve the interaction of the membrane-distal, or N-terminal heptad repeat (NHR) (termed HR1) of the cleaved S2 segment of the protein, and the membrane-proximal, or C-terminal heptad repeat (CHR) (termed HR2) regions of the protein. Following the observations of Xia et al (Xia S, Liu M, Wang C, Xu W, Lan Q, Feng S, Qi F, Bao L, Du L, Liu S, Qin C, Sun F, Shi Z, Zhu Y, Jiang S, Lu L. Cell Res. 2020b Apr;30(4):343-355), we examined the fusion inhibitory activity of a PEGylated HR2-derived peptide and its palmitoylated derivative, using a pseudovirus infection assay. The latter peptide caused a 76% reduction in fusion activity at 10 M. Our results suggest that small variations in peptide derivatization and differences in the membrane composition of pseudovirus preparations may affect the inhibitory potency of HR2-derived peptides.
Subject(s)
Hepatitis C, ChronicABSTRACT
Background: Inhaled budesonide benefits patients with COVID 19. ProLung budesonide enables the sustained, low dose administration of budesonide within a delivery vehicle similar to lung surfactant. ProLung budesonide may offer anti-inflammatory and protective effects to the lung in COVID 19, yet its effect on SARS CoV 2 replication is unknown. Objective: To determine the efficacy of ProLung budesonide against SARS CoV 2 infection in vitro, evaluate its ability to decrease inflammation, and airway hyperresponsiveness in an animal model of lung inflammation. Methods: SARS CoV 2 infected Vero 76 cells were treated with ProLung budesonide ([0.03 to 100 ug/ml]) for 3 days, and virus yield in the supernatant was measured. Ovalbumin-sensitized C57BL/6 mice received aerosolized (a) ProLung budesonide weekly, (b) only budesonide, either daily or weekly, or (c) weekly empty ProLung carrier (without budesonide). All treatment groups were compared to sensitized untreated, or normal mice using histopathologic examination, electron microscopy (EM), airway hyperresponsiveness (AHR) to Methacholine (Mch) challenge, and eosinophil peroxidase activity (EPO) measurements in bronchioalveolar lavage (BAL). Results: ProLung budesonide showed significant inhibition on viral replication of SARS CoV 2 infected cells with the selectivity index (SI) value > 24. Weekly ProLung budesonide and daily budesonide therapy significantly decreased lung inflammation and EPO in BAL. ProLung budesonide localized in type II pneumocytes, and was the only group to significantly decrease AHR, and EPO in BAL with Mch challenge. Conclusions: ProLung budesonide significantly inhibited viral replication in SARS CoV 2 infected cells. It localized into type II pneumocytes, decreased lung inflammation, AHR and EPO activity with Mch challenge. This novel drug formulation may offer a potential inhalational treatment for COVID 19.