Next Article in Journal
Recent Advances in the Synthesis and Biological Applications of Prenylated Chalcones
Previous Article in Journal
Utilization of Aflatoxin-B1-Contaminated Corn by Yellow Mealworm Larvae for Common Carp Feed and Assessing Residual Frass Toxicity by Zebrafish Embryo Microinjection
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 26
Issue 20
10.3390/ijms26209853
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Human Small Airway Epithelia Reveal Dichloroacetate as a Broad-Spectrum Antiviral Against Respiratory Viruses

by
Paula Martínez de Iturrate
1,†,
Bruno Hernáez
2,*,†,
Patricia de los Santos
1,
Yolanda Sierra-Palomares
1,
Alba García-Gómez
1,
Alonso Sánchez-Cruz
1,
Catalina Hernández-Sánchez
1,3,
Luis Rivas
1,
Margarita del Val
2 and
Eduardo Rial
1,*
1
Centro de Investigaciones Biológicas Margarita Salas, CSIC, 28040 Madrid, Spain
2
Centro de Biología Molecular Severo Ochoa, CSIC-UAM, 28049 Madrid, Spain
3
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM-ISCIII), 28034 Madrid, Spain
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2025, 26(20), 9853; https://doi.org/10.3390/ijms26209853
Submission received: 5 September 2025 / Revised: 3 October 2025 / Accepted: 9 October 2025 / Published: 10 October 2025
(This article belongs to the Special Issue Molecular Mechanisms and Treatments Targeting Respiratory Diseases)
Browse Figure
Versions Notes

Abstract

Respiratory viral infections are a major cause of morbidity and mortality worldwide. The COVID-19 pandemic has evidenced the need for broad-spectrum antivirals and improved preclinical models that more accurately recapitulate human respiratory disease. These new strategies should also involve the search for drug targets in the infected cell that hamper the development of resistance and of potential efficacy against diverse viruses. Since many viruses reprogram cellular metabolism to support viral replication, we performed a comparative analysis of inhibitors targeting the PI3K/AKT/mTOR pathway, central to virus-induced metabolic adaptations, using MRC5 lung fibroblasts and Huh7 hepatoma cells. HCoV-229E infection in MRC5 cells caused the expected shift in the energy metabolism but the inhibitors had markedly different effects on the metabolic profile and antiviral activity in these two cell lines. Dichloroacetate (DCA), a clinically approved inhibitor of aerobic glycolysis, showed antiviral activity against HCoV-229E in MRC5 cells, but not in Huh7 cells, underscoring that the screening model is more critical than previously assumed. We further tested DCA in polarized human small airway epithelial cells cultured in air–liquid interface, a 3D model that mimics the human respiratory tract. DCA reduced the viral progeny of HCoV-229E, SARS-CoV-2, and respiratory syncytial virus by 2–3 orders of magnitude, even when administered after infection was established. Our work reinforces the need for advanced human preclinical screening models to identify antivirals that target host metabolic pathways frequently hijacked by respiratory viruses, and establishes DCA as a proof-of-concept candidate.
Keywords: coronavirus; respiratory syncytial virus; respiratory infection; small airway epithelia; energy metabolism; dichloroacetate; antiviral coronavirus; respiratory syncytial virus; respiratory infection; small airway epithelia; energy metabolism; dichloroacetate; antiviral
Graphical Abstract

Share and Cite

MDPI and ACS Style

Martínez de Iturrate, P.; Hernáez, B.; de los Santos, P.; Sierra-Palomares, Y.; García-Gómez, A.; Sánchez-Cruz, A.; Hernández-Sánchez, C.; Rivas, L.; del Val, M.; Rial, E. Human Small Airway Epithelia Reveal Dichloroacetate as a Broad-Spectrum Antiviral Against Respiratory Viruses. Int. J. Mol. Sci. 2025, 26, 9853. https://doi.org/10.3390/ijms26209853

AMA Style

Martínez de Iturrate P, Hernáez B, de los Santos P, Sierra-Palomares Y, García-Gómez A, Sánchez-Cruz A, Hernández-Sánchez C, Rivas L, del Val M, Rial E. Human Small Airway Epithelia Reveal Dichloroacetate as a Broad-Spectrum Antiviral Against Respiratory Viruses. International Journal of Molecular Sciences. 2025; 26(20):9853. https://doi.org/10.3390/ijms26209853

Chicago/Turabian Style

Martínez de Iturrate, Paula, Bruno Hernáez, Patricia de los Santos, Yolanda Sierra-Palomares, Alba García-Gómez, Alonso Sánchez-Cruz, Catalina Hernández-Sánchez, Luis Rivas, Margarita del Val, and Eduardo Rial. 2025. "Human Small Airway Epithelia Reveal Dichloroacetate as a Broad-Spectrum Antiviral Against Respiratory Viruses" International Journal of Molecular Sciences 26, no. 20: 9853. https://doi.org/10.3390/ijms26209853

APA Style

Martínez de Iturrate, P., Hernáez, B., de los Santos, P., Sierra-Palomares, Y., García-Gómez, A., Sánchez-Cruz, A., Hernández-Sánchez, C., Rivas, L., del Val, M., & Rial, E. (2025). Human Small Airway Epithelia Reveal Dichloroacetate as a Broad-Spectrum Antiviral Against Respiratory Viruses. International Journal of Molecular Sciences, 26(20), 9853. https://doi.org/10.3390/ijms26209853

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Article metric data becomes available approximately 24 hours after publication online.
Back to TopTop