Combination of Remdesivir and Ivermectin Exerts Highly Potent and Synergistic Antiviral Activity Against Murine Coronavirus and SARS-CoV-2 Infections
et al., Cells, doi:10.3390/cells15131146, Jun 2026
Ivermectin for COVID-19
4th treatment shown to reduce risk in
August 2020, now with p < 0.00000000001 from 106 studies, recognized in 24 countries.
No treatment is 100% effective. Protocols
combine treatments.
6,600+ studies for
220+ treatments. c19early.org
|
In vitro study showing synergistic antiviral activity of ivermectin and remdesivir against murine coronavirus (MHV) and SARS-CoV-2.
76 preclinical studies support the efficacy of ivermectin for COVID-19:
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N773, Dengue38,74,75 , HIV-175, Simian virus 4076, Zika38,77,78 , West Nile78, Yellow Fever79,80, Japanese encephalitis79, Chikungunya80, Semliki Forest virus80, Human papillomavirus58, Epstein-Barr58, BK Polyomavirus81, and Sindbis virus80.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins73,75,76,82 , shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing39, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination42,83, shows dose-dependent inhibition of wildtype and omicron variants37, exhibits dose-dependent inhibition of lung injury63,68, may inhibit SARS-CoV-2 via IMPase inhibition38, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation10, inhibits SARS-CoV-2 3CLpro55, may inhibit SARS-CoV-2 RdRp activity1,29, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages62, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation84, may interfere with SARS-CoV-2's immune evasion via ORF8 binding5, may inhibit SARS-CoV-2 by disrupting CD147 interaction85-88, may inhibit SARS-CoV-2 attachment to lipid rafts via spike NTD binding3, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1960,89, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage9, significantly mitigates bleomycin-induced pulmonary fibrosis by reducing collagen accumulation and inflammatory cell infiltration61, improves oxidative stress markers while suppressing myofibroblast proliferation61, may minimize SARS-CoV-2 induced cardiac damage41,49, may counter immune evasion by inhibiting NSP15-TBK1/KPNA1 interaction and restoring IRF3 activation90, may disrupt SARS-CoV-2 N and ORF6 protein nuclear transport and their suppression of host interferon responses2, reduces TAZ/YAP nuclear import, relieving SARS-CoV-2-driven suppression of IRF3 and NF-κB antiviral pathways36, increases Bifidobacteria which play a key role in the immune system91, has immunomodulatory52 and anti-inflammatory72,92 properties, and has an extensive and very positive safety profile93.
Study covers ivermectin and remdesivir.
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Lew et al., 24 Jun 2026, USA, peer-reviewed, 10 authors.
Contact: kaistan@nus.edu.sg (corresponding author), zzlew@u.nus.edu, douglastay@nus.edu.sg, miccjh@nus.edu.sg, entwdy@nus.edu.sg, jocelyn_ong_wen_xin@immunol.a-star.edu.sg, low_jing_hui@immunol.a-star.edu.sg, anand_andiappan@immunol.a-star.edu.sg, entliuj@nus.edu.sg, micctk@nus.edu.sg.
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
Abstract:
Article
Combination of Remdesivir and Ivermectin Exerts Highly Potent and Synergistic Antiviral Activity Against Murine Coronavirus and SARS-CoV-2 Infections
Ryan Z. Z. Lew 1,2,3 , Douglas J. W. Tay 1,2,3 , Jocelyn W. X. Ong 4 , Jing Hui Low 4 , Jing Liu 5 , De Yun Wang 3,5 , Justin J. H. Chu 1,2,3 , Anand Kumar Andiappan 4 , Kai Sen Tan 1,2,3, * and Vincent T. K. Chow 1,3, *
- 1 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore 117545, Singapore; zzlew@u.nus.edu (R.Z.Z.L.); douglastay@nus.edu.sg (D.J.W.T.); miccjh@nus.edu.sg (J.J.H.C.)
- 2 NUS Medicine Biosafety Level 3 Core Facility, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore 117599, Singapore
- 3 Infectious Diseases Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore 117597, Singapore; entwdy@nus.edu.sg
- 4 Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis, Singapore 138648, Singapore; jocelyn\_ong\_wen\_xin@immunol.a-star.edu.sg (J.W.X.O.); low\_jing\_hui@immunol.a-star.edu.sg (J.H.L.); anand\_andiappan@immunol.a-star.edu.sg (A.K.A.)
- 5 Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore 119228, Singapore; entliuj@nus.edu.sg
* Correspondence: kaistan@nus.edu.sg (K.S.T.); micctk@nus.edu.sg (V.T.K.C.)
Abstract
The COVID-19 pandemic highlighted the urgent need to develop effective and broadspectrum antiviral therapies against coronaviruses. One strategy to address this concern is a combination therapy using repurposed drugs against zoonotic viruses with pandemic potential. We previously demonstrated that the combination of Remdesivir and Ivermectin is highly potent and synergistic in inhibiting the replication of murine hepatitis virus (MHV) in RAW264.7 macrophages. This study investigated the interactions between the drug combination, coronavirus and host by proteomics and RNA sequencing of MHV-infected H2.35 murine liver epithelial cells. Time-of-addition and time-of-removal assays suggested that the drug combination likely affected the synthesis of viral RNA and viral protein. This combination drastically diminished the live virus titer greater than the respective monotherapies in MHV-infected H2.35 cells (by ~4 log10), as well as in SARS-CoV-2-infected VeroE6 cells and human nasal epithelial cells. Proteomic and transcriptomic analyses revealed that viral protein and RNA levels were significantly depressed upon combination treatment. The drug combination exhibited considerable negative effects upon host RNA processes and resulted in the upregulation of host protein processes (e.g., response to unfolded protein; protein insertion into ER membrane). Molecular pathways affected by the combination treatment were markedly distinct from the monotherapies and indicated that Ivermectin enhances Remdesivir by modulating critical host processes to synergistically exert its inhibitory effect on the coronavirus replication cycle.
Keywords: Remdesivir; Ivermectin; combination therapy; repurposed drugs; murine hepatitis virus; SARS-CoV-2; proteomics; transcriptomics; host pathways
Academic Editor: Shih-Heng (David) Chen
Received: 4 May 2026
Revised: 10 June 2026
Accepted: 21 June 2026
Published: 24 June 2026
Copyright:
©2026 by the authors.
Licensee MDPI, Basel, Switzerland.
This..
DOI record:
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"DOI": "10.3390/cells15131146",
"ISSN": [
"2073-4409"
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"URL": "http://dx.doi.org/10.3390/cells15131146",
"abstract": "<jats:p>The COVID-19 pandemic highlighted the urgent need to develop effective and broad-spectrum antiviral therapies against coronaviruses. One strategy to address this concern is a combination therapy using repurposed drugs against zoonotic viruses with pandemic potential. We previously demonstrated that the combination of Remdesivir and Ivermectin is highly potent and synergistic in inhibiting the replication of murine hepatitis virus (MHV) in RAW264.7 macrophages. This study investigated the interactions between the drug combination, coronavirus and host by proteomics and RNA sequencing of MHV-infected H2.35 murine liver epithelial cells. Time-of-addition and time-of-removal assays suggested that the drug combination likely affected the synthesis of viral RNA and viral protein. This combination drastically diminished the live virus titer greater than the respective monotherapies in MHV-infected H2.35 cells (by ~4 log10), as well as in SARS-CoV-2-infected VeroE6 cells and human nasal epithelial cells. Proteomic and transcriptomic analyses revealed that viral protein and RNA levels were significantly depressed upon combination treatment. The drug combination exhibited considerable negative effects upon host RNA processes and resulted in the upregulation of host protein processes (e.g., response to unfolded protein; protein insertion into ER membrane). Molecular pathways affected by the combination treatment were markedly distinct from the monotherapies and indicated that Ivermectin enhances Remdesivir by modulating critical host processes to synergistically exert its inhibitory effect on the coronavirus replication cycle.</jats:p>",
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"name": "Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore 117545, Singapore"
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"name": "NUS Medicine Biosafety Level 3 Core Facility, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore 117599, Singapore"
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