1. Antiviral activity of oleandrin and a defined extract of Nerium oleander against SARS-CoV-2
- Author
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Rick Matos, Divya Mirchandani, Scott C. Weaver, Diana Fernández, Jordi B. Torrelles, Varun Dwivedi, Jennifer Delgado, Nathen E. Bopp, Kenneth S. Plante, Vinay Shivanna, Patricia V. Aguilar, Jun Gyu Park, Luis Martinez-Sobrido, Jessica A. Plante, Paula Pino Tamayo, Robert A. Newman, K. Jagannadha Sastry, The University of Texas Medical Branch (UTMB), World Reference Center for Emerging Viruses and Arboviruses (WRCEVA), Institute for Human Infections and Immunity and Department of Pathology, Texas Biomedical Research Institute [San Antonio, TX], Innovar LLC, Phoenix Biotechnology, Inc., The University of Texas M.D. Anderson Cancer Center [Houston], and This research was supported in part by NIH grant R24 AI120942 to SCW. We thank Natalie Thornburg (Centers 305 for Disease Control and Prevention, Atlanta, GA, USA) and the World Reference Center for Emerging Viruses and Arboviruses for providing the SARS-CoV-2 USA_WA1/2020 isolate. Research was also supported by Phoenix Biotechnology, Inc. Experimental design, conduct of the experiments, and interpretation of the data were the independent products of scientists at University of Texas Medical Branch (Galveston) and Texas Biomedical Research Institute with consulting comments from R. A. Newman, PhD, and K. Jagannadha Sastry, PhD. The authors thank Bev Newman, M.S., R.N. for graphic art support.
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0301 basic medicine ,Oleandrin ,NP, nucleocapsid protein ,LDH, lactic dehydrogenase ,[SDV]Life Sciences [q-bio] ,DPI, day post infection ,Pharmacology ,DMSO, dimethyl sulfoxide ,medicine.disease_cause ,law.invention ,chemistry.chemical_compound ,0302 clinical medicine ,HTLV-1, human T-lymphotropic virus ,law ,Cricetinae ,Chlorocebus aethiops ,Mab, monoclonal antibody ,Antiviral activity ,Coronavirus ,General Medicine ,3. Good health ,HIV, human immunodeficiency virus ,Cardenolides ,Titer ,CPE, cytopathic effect ,Reduced infectivity ,030220 oncology & carcinogenesis ,BDNF, brain-derived neurotrophic factor ,EC50, half maximal effective concentration ,Female ,Original Article ,ATP, adenosine triphosphate ,ALT, alanine transaminase ,Genome, Viral ,RM1-950 ,Antiviral Agents ,Virus ,MERS, middle east respiratory syndrome ,03 medical and health sciences ,FBS, fetal bovine serum ,In vivo ,medicine ,DPBS, Dulbecco’s phosphate-buffered saline ,Animals ,Nerium ,SARS, severe acute respiratory syndrome ,Vero Cells ,EC50 ,ELISA, enzyme-linked immunoassay ,ALP, alkaline phosphatase ,Plant Extracts ,business.industry ,SARS-CoV-2 ,COVID-19 ,Nrf-2, nuclear factor erythroid 2-related factor 2 ,Nerium oleander ,COVID-19 Drug Treatment ,030104 developmental biology ,chemistry ,qRT-PCR, real-time quantitative polymerase chain reaction ,Vero cell ,RNA, ribonucleic acid ,H&E, hematoxylin and eosin ,BSA, bovine serum albumin ,Therapeutics. Pharmacology ,business ,Phytotherapy ,PFU, plaque-forming unit - Abstract
International audience; 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 0.05g/ml exhibited potent antiviral activity against SARS-CoV-2, with an 800-fold reduction in virus production, and a 0.1g/ml concentration resulted in a greater than 3000-fold reduction in infectious virus production. The half maximal effective concentration (EC50) values were 11.98ng/ml when virus output was measured at 24h post-infection, and 7.07ng/ml measured at 48h post-infection. Therapeutic (post-infection) treatment up to 24h after SARS-CoV-2 infection of Vero cells also reduced viral titers, with 0.1g/ml and 0.05g/ml concentrations causing greater than 100-fold reduction as measured at 48h, and the 0.05g/ml concentration resulting in a 78-fold reduction. Concentrations of oleandrin up to 10g/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 130g/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.
- Published
- 2021
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