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Pharmacokinetic-based failure of a detergent virucidal for SARS-COV-2 nasal infections.

ABSTRACT: The nose is the portal for SARS-CoV-2 infection, suggesting the nose as a target for topical antiviral therapies. Because detergents are virucidal, Johnson and Johnson's Baby Shampoo (J&J) was tested as a topical virucidal agent in SARS-CoV-2 infected subjects. Twice daily irrigation of J&J in hypertonic saline, hypertonic saline alone, or no intervention were compared (n = 24/group). Despite demonstrated safety and robust efficacy in in vitro virucidal assays, J&J irrigations had no impact on viral titers or symptom scores in treated subjects relative to controls. Similar findings were observed administering J&J to infected cultured human airway epithelia using protocols mimicking the clinical trial regimen. Additional studies of cultured human nasal epithelia demonstrated that lack of efficacy reflected pharmacokinetic failure, with the most virucidal J&J detergent components rapidly absorbed from nasal surfaces. This study emphasizes the need to assess the pharmacokinetic characteristics of virucidal agents on airway surfaces to guide clinical trials.

SUBMITTER: Esther CR

PROVIDER: S-EPMC8132247 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Pharmacokinetic-based failure of a detergent virucidal for SARS-COV-2 nasal infections.

Esther Charles R CR Kimura Kyle S KS Mikami Yu Y Edwards Caitlin E CE Das Suman R SR Freeman Michael H MH Strickland Britton A BA Brown Hunter M HM Wessinger Bronson C BC Gupta Veerain C VC Von Wahlde Kate K Sheng Quanhu Q Huang Li Ching LC Bacon Daniel R DR Kimple Adam J AJ Ceppe Agathe S AS Kato Takafumi T Pickles Raymond J RJ Randell Scott H SH Baric Ralph S RS Turner Justin H JH Boucher Richard C RC

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The nose is the portal for SARS-CoV-2 infection, suggesting the nose as a target for topical antiviral therapies. Because detergents are virucidal, Johnson and Johnson's Baby Shampoo (J&J) was tested as a topical virucidal agent in SARS-CoV-2 infected subjects. Twice daily irrigation of J&J in hypertonic saline, hypertonic saline alone, or no intervention were compared (n = 24/group). Despite demonstrated safety and robust efficacy in <i>in vitro</i> virucidal assays, J&J irrigations had no impa ...[more]

PMID: 34013253

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Project description:A global pandemic is underway caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 genome, like its predecessor SARS-CoV, contains open reading frames that encode accessory proteins involved in virus-host interactions active during infection and which likely contribute to pathogenesis. One of these accessory proteins is 7b, with only 44 (SARS-CoV) and 43 (SARS-CoV-2) residues. It has one predicted transmembrane domain fully conserved, which suggests a functional role, whereas most variability is contained in the predicted cytoplasmic C-terminus. In SARS-CoV, 7b protein is expressed in infected cells, and the transmembrane domain was necessary and sufficient for Golgi localization. Also, anti-p7b antibodies have been found in the sera of SARS-CoV convalescent patients. In the present study, we have investigated the hypothesis that SARS-2 7b protein forms oligomers with ion channel activity. We show that in both SARS viruses 7b is almost completely α-helical and has a single transmembrane domain. In SDS, 7b forms various oligomers, from monomers to tetramers, but only monomers when exposed to reductants. Combination of SDS gel electrophoresis and analytical ultracentrifugation (AUC) in both equilibrium and velocity modes suggests a dimer-tetramer equilibrium, but a monomer–dimer–tetramer equilibrium in the presence of reductant. This data suggests that although disulfide-linked dimers may be present, they are not essential to form tetramers. Inclusion of pentamers or higher oligomers in the SARS-2 7b model were detrimental to fit quality. Preliminary models of this association was generated with AlphaFold2, and two alternative models were exposed to a molecular dynamics simulation in presence of a model lipid membrane. However, neither of the two models provided any evident pathway for ions. To confirm this, SARS-2 p7b was studied using Planar Bilayer Electrophysiology. Addition of p7b to model membranes produced occasional membrane permeabilization, but this was not consistent with bona fide ion channels made of a tetrameric assembly of α-helices. Supplementary Information The online version contains supplementary material available at 10.1186/s12985-022-01920-0.

Dataset Information

Pharmacokinetic-based failure of a detergent virucidal for SARS-COV-2 nasal infections.

Publications

Pharmacokinetic-based failure of a detergent virucidal for SARS-COV-2 nasal infections.

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