Inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 Replication by Hypertonic Saline Solution in Lung and Kidney Epithelial Cells

Machado, Rafael; Glaser, Talita; Araújo, Danielle Bastos; Petiz, Lyvia Lintzmaier; Oliveira, Danielle Bruna Leal; Durigon, Giuliana Stravinskas; Leal, Alessandra Lima; Pinho, J R R; Ferreira, Luís Carlos S.; Ulrich, Henning; Durigon, Edison Luiz; Guzzo, Cristiane R.

doi:10.1021/acsptsci.1c00080

Cited by 23 publications

(28 citation statements)

References 67 publications

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“…Hyponatremia where plasma sodium concentration is below 135 mmol/L is often associated with viral infections including COVID-19 [ 422 ]. Furthermore, in vitro experiments found 1.5% NaCl solution can achieve 100% inhibition of SARS-CoV-2 replication in nonhuman primate kidney Vero cells, while 1.1% of NaCl can inhibit viral replication by 88% in human epithelia lung Calu-3 cells [ 423 ].…”

Section: Melatonin Protects Mitochondria and Atp Production To Inhibi...mentioning

confidence: 99%

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Loh¹,

Reíter

2022

IJMS

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The relentless, protracted evolution of the SARS-CoV-2 virus imposes tremendous pressure on herd immunity and demands versatile adaptations by the human host genome to counter transcriptomic and epitranscriptomic alterations associated with a wide range of short- and long-term manifestations during acute infection and post-acute recovery, respectively. To promote viral replication during active infection and viral persistence, the SARS-CoV-2 envelope protein regulates host cell microenvironment including pH and ion concentrations to maintain a high oxidative environment that supports template switching, causing extensive mitochondrial damage and activation of pro-inflammatory cytokine signaling cascades. Oxidative stress and mitochondrial distress induce dynamic changes to both the host and viral RNA m6A methylome, and can trigger the derepression of long interspersed nuclear element 1 (LINE1), resulting in global hypomethylation, epigenetic changes, and genomic instability. The timely application of melatonin during early infection enhances host innate antiviral immune responses by preventing the formation of “viral factories” by nucleocapsid liquid-liquid phase separation that effectively blockades viral genome transcription and packaging, the disassembly of stress granules, and the sequestration of DEAD-box RNA helicases, including DDX3X, vital to immune signaling. Melatonin prevents membrane depolarization and protects cristae morphology to suppress glycolysis via antioxidant-dependent and -independent mechanisms. By restraining the derepression of LINE1 via multifaceted strategies, and maintaining the balance in m6A RNA modifications, melatonin could be the quintessential ancient molecule that significantly influences the outcome of the constant struggle between virus and host to gain transcriptomic and epitranscriptomic dominance over the host genome during acute infection and PASC.

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Section: Melatonin Protects Mitochondria and Atp Production To Inhibi...mentioning

confidence: 99%

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Loh¹,

Reíter

2022

IJMS

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“…The major mechanism is possibly through sodium ion-mediated intracellular low energy states [15]. In this study, we observed that hypertonic saline can significantly block SARS-CoV-2specific FCS cleavage caused by furin but not by trypsin.…”

Section: Discussionmentioning

confidence: 56%

Hypertonic saline and aprotinin based blockage of SARS-CoV-2 specific furin site cleavage by inhibition of nasal protease activity

A¹,

Li²

2021

Preprint

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SARS-CoV-2 enters into the human body mainly through the nasal epithelial cells. Cell entry of SARS-CoV-2 needs to be pre-activated by S1/S2 boundary furin motif cleavage by furin and/or relevant proteases. It is important to locally block SARS-CoV-2 S1/S2 site cleavage caused by furin and other relevant protease activity in the nasal cavity. We tested hypertonic saline and aprotinin-based blockage of SARS-CoV-2 specific furin site cleavage by furin, trypsin and nasal swab samples containing nasal proteases. Our results show that saline and aprotinin block SARS-Cov-2 specific furin site cleavage and that a saline and aprotinin combination could significantly reduce SARS-Cov-2 wild-type and P681R mutant furin site cleavage by inhibition of nasal protease activity.

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“…The major mechanism was possibly through sodium ion-mediated intracellular low energy states. 16 In this study, we observed that in both the wildtype and mutants, hypertonic saline could significantly block the SARS-CoV-2-specific FCS cleavage caused by furin but not by trypsin. As S protein cleavage played a critical role in the SARS-CoV-2 activation before entry into and exiting from the cells, the inhibitory effect of hypertonic saline on the SARS-CoV-2 replication could be at least partly due to the blockage of the furin-mediated cleavage.…”

Section: Discussionmentioning

confidence: 61%

Hypertonic Saline and Aprotinin Inhibit Furin and Nasal Protease to Reduce SARS-CoV-2 Specific Furin Site Cleavage Activity

Li¹,

Li²

2022

J Explor Res Pharmacol

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Background and objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the human body mainly through the nasal epithelial cells. The cell entry of SARS-CoV-2 needs to be preactivated via S1/S2 boundary furin motif cleavage by furin and/or relevant proteases. Therefore, it is important to locally block the SARS-CoV-2 S1/S2 site cleavage caused by furin and other relevant protease activity in the nasal cavity.Methods: With synthesized peptides containing a wild-type or mutant furin cleavage motif and by using SARS-CoV-2 specific furin site cleavage assay, we tested the hypertonic saline and aprotinin-based blockage of the SARS-CoV-2 specific furin site cleavage by furin, trypsin, and nasal swab samples containing nasal proteases. Results:The results showed that hypertonic saline and aprotinin could block SARS-CoV-2 specific furin site cleavage, and a hypertonic saline and aprotinin combination could reduce 99% of the furin site cleavage in the SARS-CoV-2 wild-type, 90% in the P681R mutant, and 83% in the N679K/P681H mutants, respectively by inhibition of the nasal protease activity. Conclusions:Our findings preliminarily elucidated that the combination of hypertonic saline and aprotinin significantly blocked the furin site cleavage in both the SARS-CoV-2 wild-type and mutants (P681R and N679K/P681H), which could represent a simple, economical, and practical feasible approach in locally controlling viral activation and entry into cells to replicate.

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Inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 Replication by Hypertonic Saline Solution in Lung and Kidney Epithelial Cells

Cited by 23 publications

References 67 publications

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Hypertonic saline and aprotinin based blockage of SARS-CoV-2 specific furin site cleavage by inhibition of nasal protease activity

Hypertonic Saline and Aprotinin Inhibit Furin and Nasal Protease to Reduce SARS-CoV-2 Specific Furin Site Cleavage Activity

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