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Antiviral activity of oleandrin and a defined extract of Nerium oleander against SARS-CoV-2 - 16/04/21

Doi : 10.1016/j.biopha.2021.111457 
Kenneth S. Plante a, b, c, 1, Varun Dwivedi d, 1, Jessica A. Plante a, b, c, Diana Fernandez a, b, e, Divya Mirchandani a, b, c, Nathen Bopp a, b, c, Patricia V. Aguilar a, b, c, f, Jun-Gyu Park d, Paula Pino Tamayo d, Jennifer Delgado d, Vinay Shivanna d, Jordi B. Torrelles d, Luis Martinez-Sobrido d, Rick Matos h, j, Scott C. Weaver a, b, c, f, 1, K. Jagannadha Sastry g, 1, Robert A. Newman i, j, , 1
a World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX 77555, USA 
b Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA 
c Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA 
d Population Health and Host-Pathogens Interactions Programs, Texas Biomedical Research Institute, San Antonio, TX 78227, USA 
e Center for Tropical Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA 
f Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA 
g Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 
h Innovar, LLC, Plano, TX 75025, USA 
i Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 
j Phoenix Biotechnology, Inc., San Antonio, TX 78217, USA 

Correspondence to: Phoenix Biotechnology, Inc., 8626 Tesoro Dr., Suite 801, San Antonio, TX 78217, USA.Phoenix Biotechnology, Inc.8626 Tesoro Dr., Suite 801San AntonioTX78217USA

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Abstract

With continued expansion of the coronavirus disease (COVID-19) pandemic, caused by severe acute respiratory syndrome 2 (SARS-CoV-2), both antiviral drugs as well as effective vaccines are desperately needed to treat patients at high risk of life-threatening disease. Here, we present in vitro evidence for significant inhibition of SARS-CoV-2 by oleandrin and a defined extract of N. oleander (designated as PBI-06150). Using Vero cells, we found that prophylactic (pre-infection) oleandrin (as either the pure compound or as the active principal ingredient in PBI-06150) administration at concentrations as low as 0.05 µg/ml exhibited potent antiviral activity against SARS-CoV-2, with an 800-fold reduction in virus production, and a 0.1 µg/ml concentration resulted in a greater than 3000-fold reduction in infectious virus production. The half maximal effective concentration (EC50) values were 11.98 ng/ml when virus output was measured at 24 h post-infection, and 7.07 ng/ml measured at 48 h post-infection. Therapeutic (post-infection) treatment up to 24 h after SARS-CoV-2 infection of Vero cells also reduced viral titers, with 0.1 µg/ml and 0.05 µg/ml concentrations causing greater than 100-fold reduction as measured at 48 h, and the 0.05 µg/ml concentration resulting in a 78-fold reduction. Concentrations of oleandrin up to 10 µg/ml were well tolerated in Vero cells. We also present in vivo evidence of the safety and efficacy of defined N. oleander extract (PBI-06150), which was administered to golden Syrian hamsters in a preparation containing as high as 130 µg/ml of oleandrin. In comparison to administration of control vehicle, PBI-06150 provided a statistically significant reduction of the viral titer in the nasal turbinates (nasal conchae). The potent prophylactic and therapeutic antiviral activities demonstrated here, together with initial evidence of its safety and efficacy in a relevant hamster model of COVID-19, support the further development of oleandrin and/or defined extracts containing this molecule for the treatment of SARS-CoV-2 and associated COVID-19 disease and potentially also for reduction of virus spread by persons diagnosed early after infection.

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Highlights

Strong antiviral activity against “enveloped” viruses including coronaviruses.
Oleander shows significant antiviral effect against SARS-CoV-2 in Vero cells.
Oleandrin prevents as well as effectively treats SARS-CoV-2 infected Vero cells.
PBI-06150 was tested in vivo in an established hamster COVID-19 model.
Antiviral effect documented as reduction in tracheal tissue viral load.

Le texte complet de cet article est disponible en PDF.

Abbreviations : SARS, MERS, HIV, HTLV-1, Mab, NP, BSA, DPI, DMSO, CPE, PFU, EC50, ATP, Nrf-2, BDNF, FBS, LDH, DPBS, qRT-PCR, RNA, ALT, ALP, ELISA, H&E

Keywords : Oleandrin, Nerium oleander, SARS-CoV-2, COVID-19, Antiviral activity, Reduced infectivity


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© 2021  The Authors. Publié par Elsevier Masson SAS. Tous droits réservés.
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