Bromhexine inhibits SARS-CoV-2 Omicron and variant pseudovirus infection via ACE2-targeted mechanisms
et al., Frontiers in Pharmacology, doi:10.3389/fphar.2025.1745277, Jan 2026
In vitro study showing that bromhexine inhibits SARS-CoV-2 Omicron and variant pseudovirus infection via ACE2-targeted mechanisms. Authors found that the antiviral mechanism involves destabilization of the SARS-CoV-2 spike-ACE2 interface, preventing viral entry through direct disruption of virus-host receptor interaction rather than solely through TMPRSS2 inhibition. The consistent effectiveness across multiple variants suggests bromhexine's potential as a broad-spectrum entry inhibitor for current and emerging SARS-CoV-2 variants.
Bromhexine efficacy may vary depending on the degree of TMPRSS-dependent fusion for different variants1,2.
6 preclinical studies support the efficacy of bromhexine for COVID-19:
In silico studies predict inhibition of SARS-CoV-2 with bromhexine or metabolites via binding to the spikeA,3, MproB,3, RNA-dependent RNA polymeraseC,3, and TMPRSS2D,4 proteins.
In vitro studies demonstrate inhibition of the TMPRSS2D,6 and acid sphingomyelinaseE,7 proteins.
Bromhexine is a mucolytic agent that helps thin mucus
secretions in the respiratory tract and has been shown to have antiviral
properties against respiratory viruses.
Bromhexine inhibits the expression of TMPRSS2 which plays an important role in SARS-CoV-2 cell entry and replication4,6,8 , may prevent SARS-CoV-2 infection by disrupting spike-ACE2 binding through direct interaction with the ACE2 receptor5, and bromhexine metabolite ambroxol inhibits SARS-CoV-2 via inhibition of acid sphingomyelinase in epithelial cells7.
1.
Willett et al., The hyper-transmissible SARS-CoV-2 Omicron variant exhibits significant antigenic change, vaccine escape and a switch in cell entry mechanism, medRxiv, doi:10.1101/2022.01.03.21268111.
2.
Peacock et al., The SARS-CoV-2 variant, Omicron, shows rapid replication in human primary nasal epithelial cultures and efficiently uses the endosomal route of entry, bioRxiv, doi:10.1101/2021.12.31.474653.
3.
Haque et al., Exploring potential therapeutic candidates against COVID-19: a molecular docking study, Discover Molecules, doi:10.1007/s44345-024-00005-5.
4.
Sgrignani et al., Computational Identification of a Putative Allosteric Binding Pocket in TMPRSS2, Frontiers in Molecular Biosciences, doi:10.3389/fmolb.2021.666626.
5.
Zúñiga et al., Bromhexine inhibits SARS-CoV-2 Omicron and variant pseudovirus infection via ACE2-targeted mechanisms, Frontiers in Pharmacology, doi:10.3389/fphar.2025.1745277.
6.
Martins et al., In Vitro Inhibition of SARS-CoV-2 Infection by Bromhexine hydrochloride, bioRxiv, doi:10.1101/2022.12.23.521817.
a.
The trimeric spike (S) protein is a glycoprotein that mediates viral entry by binding to the host ACE2 receptor, is critical for SARS-CoV-2's ability to infect host cells, and is a target of neutralizing antibodies. Inhibition of the spike protein prevents viral attachment, halting infection at the earliest stage.
b.
The main protease or Mpro, also known as 3CLpro or nsp5, is a cysteine protease that cleaves viral polyproteins into functional units needed for replication. Inhibiting Mpro disrupts the SARS-CoV-2 lifecycle within the host cell, preventing the creation of new copies.
c.
RNA-dependent RNA polymerase (RdRp), also called nsp12, is the core enzyme of the viral replicase-transcriptase complex that copies the positive-sense viral RNA genome into negative-sense templates for progeny RNA synthesis. Inhibiting RdRp blocks viral genome replication and transcription.
d.
Transmembrane protease serine 2 (TMPRSS2) is a host cell protease that primes the spike protein, facilitating cellular entry. TMPRSS2 activity helps enable cleavage of the spike protein required for membrane fusion and virus entry. Inhibition may especially protect respiratory epithelial cells, buy may have physiological effects.
e.
Acid sphingomyelinase (ASM) is a lysosomal enzyme that hydrolyzes sphingomyelin into ceramide and phosphorylcholine. ASM activity is upregulated by SARS-CoV-2 infection, leading to ceramide-enriched membrane domains that facilitate viral entry and replication. Inhibiting ASM may disrupt viral entry and reduce infection severity while potentially restoring membrane stability and immune homeostasis.
Zúñiga et al., 12 Jan 2026, Chile, peer-reviewed, 9 authors.
Contact: lzuniga@utalca.cl.
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
Bromhexine inhibits SARS-CoV-2 Omicron and variant pseudovirus infection via ACE2-targeted mechanisms
Frontiers in Pharmacology, doi:10.3389/fphar.2025.1745277
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a highly infectious disease characterized by fever, acute respiratory illness, and pneumonia, known as coronavirus disease 2019 (COVID-19). SARS-CoV-2 infects host cells through the interaction of its spike glycoprotein (S protein) with human angiotensin-converting enzyme 2 (hACE2). Structural studies have shown that hACE2 interacts exclusively with the receptor-binding domain (RBD) of the spike. A high binding affinity between spike and hACE2 has been linked to increased viral infection. Disrupting this interaction can reduce viral infectivity. Methods: This study aimed to assess infection using Omicron variant pseudovirus in a stable HEK-293 cell line expressing hACE2 (HEK-293/ACE2), treated with bromhexine hydrochloride. First, immunofluorescence and Western blot confirmed the presence of hACE2 in the stable line. Then, bromhexine concentrations for treatment were determined by cytotoxicity assays. Next, infection was evaluated using Omicron pseudoviruses carrying GFP and luciferase reporter genes. Infection levels were measured through fluorescence or luciferase activity. Results: Bromhexine reduced infection with an IC 50 of 17.3 ± 0.9 µM. About 40% inhibition was also observed against Alpha, Beta, and Delta variants at 40 µM. Computational docking followed by molecular dynamics simulations showed that bromhexine binds to the extracellular domain of hACE2, with recurrent contacts near Phe40, Phe390, and Asn394. Conclusion: Consistent with this model, our findings support an entry-inhibition mechanism whereby bromhexine destabilizes the SARS-CoV-2 spike-ACE2 interface, preventing viral entry. Overall, these results suggest bromhexine as a potential repurposing candidate and support its inclusion in therapeutic strategies aimed at both current and emerging SARS-CoV-2 variants.
Ethics statement Ethical approval was not required for the studies on humans in accordance with the local legislation and institutional requirements because only commercially available established cell lines were used. Ethical approval was not required for the studies on animals in accordance with the local legislation and institutional requirements because only commercially available established cell lines were used.
Author contributions
Conflict of interest The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement The author(s) declared that generative AI was not used in the creation of this manuscript. Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
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Supplementary material The Supplementary Material for this article..
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"abstract": "<jats:sec>\n <jats:title>Background</jats:title>\n <jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) causes a highly infectious disease characterized by fever, acute respiratory illness, and pneumonia, known as coronavirus disease 2019 (COVID‐19). SARS‐CoV‐2 infects host cells through the interaction of its spike glycoprotein (S protein) with human angiotensin‐converting enzyme 2 (hACE2). Structural studies have shown that hACE2 interacts exclusively with the receptor‐binding domain (RBD) of the spike. A high binding affinity between spike and hACE2 has been linked to increased viral infection. Disrupting this interaction can reduce viral infectivity.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>This study aimed to assess infection using Omicron variant pseudovirus in a stable HEK‐293 cell line expressing hACE2 (HEK‐293/ACE2), treated with bromhexine hydrochloride. First, immunofluorescence and Western blot confirmed the presence of hACE2 in the stable line. Then, bromhexine concentrations for treatment were determined by cytotoxicity assays. Next, infection was evaluated using Omicron pseudoviruses carrying GFP and luciferase reporter genes. Infection levels were measured through fluorescence or luciferase activity.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>\n Bromhexine reduced infection with an IC\n <jats:sub>50</jats:sub>\n of 17.3 ± 0.9 μM. About 40% inhibition was also observed against Alpha, Beta, and Delta variants at 40 μM. Computational docking followed by molecular dynamics simulations showed that bromhexine binds to the extracellular domain of hACE2, with recurrent contacts near Phe40, Phe390, and Asn394.\n </jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusion</jats:title>\n <jats:p>Consistent with this model, our findings support an entry‐inhibition mechanism whereby bromhexine destabilizes the SARS‐CoV‐2 spike–ACE2 interface, preventing viral entry. Overall, these results suggest bromhexine as a potential repurposing candidate and support its inclusion in therapeutic strategies aimed at both current and emerging SARS‐CoV‐2 variants.</jats:p>\n </jats:sec>",
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