Viral diseases

We recently reported (PMID: 33262663) that many investigators have now published reports on the antiviral activity of oleandrin and extracts that contain this molecule. Our products PBI-05204, PBI-01220, PBI-01207, and PBI-06150 contain oleandrin and exhibit high antiviral activity even when dosed at extremely low levels, i.e. levels well below those required for anticancer activity.

Recent research has focused on elucidation of the underlying mechanisms responsible for such activity.  The findings have been dramatic. Oleandrin asserts both therapeutic and prophylactic antiviral activity by affecting intracellular and extracellular aspects of the immune response (unpublished data).

There are many types of viruses that affect human as well as animal health and wellbeing. A number of those viruses contain an ‘outer envelope structure’ or corona (aka crown) that surrounds and protects the viral genetic material. Proper formation of the envelope is required for progeny virus to retain their infectivity.

In 2013, PBI explored the ability of oleandrin to inhibit HIV (human immunodeficiency virus), an envelope virus. A major finding in that research (PMID: 23127567) was that progeny virus particles lost a significant ability to infect new human white blood cells. We determined that within the infected cell oleandrin interfered with formation of a proper viral ‘envelope’, thereby causing formation of defective progeny virions.

It has also been determined that oleandrin impacts the intracellular unfolded protein response that occurs in virally infected cells. GRP78 is a protein that plays a key role in the unfolded protein response that occurs during periods of cellular stress. At such times, the overexpression of GRP78 on the cell membrane mediates the vast amount of disordered proteins. Unfortunately, this makes GRP78 a tool for pathogens (bacterial, fungal and viral) to enter the cell and to initiate different cellular pathways leading to pathogenesis. For example, GRP78 is overexpressed on the membranes of virally infected cells and increases the aggressiveness of the disease. This has already been established for numerous viral infections including SARS-CoV-2. In 2017, Zhao reported the effect that some small molecules have upon the cell surface translocation of GRP78. The premise of that research was that reduction of the translocation might reduce the aggressiveness of diseases relying upon the presence of cell surface GRP78. Zhao found that oleandrin inhibits cell surface translocation of GRP78, thereby pointing to that as another aspect of oleandrin’s antiviral activity.

Based upon its effect on viral envelope formation and on inhibition of GRP78 translocation, PBI developed a hypothesis that oleandrin might be effective as both a prophylactic and therapeutic agent against this broad variety of viruses.  Indeed, that is proving to be true.  These novel mechanisms of antiviral activity opened a wide door to testing the ability of oleandrin and our products to possibly serve as effective antiviral agents against a potentially wide array of enveloped viruses.

Research has been conducted on a wide assortment of viruses including Ebolavirus, Marburgvirus, cytomegalovirus, Herpes viruses (several), HTLV-1, and most recently SARS-CoV-2, the virus that causes COVID-19. That research, conducted by U.S. Army, Univ. Texas MD Anderson Cancer Center, Johns Hopkins Medical Center, Southern Methodist University and University of Texas Medical Branch’s World Reference Center for Emerging Viruses and Arboviruses, has shown that oleandrin and extracts such as PBI-05204 significantly and potently inhibit the ability of these viruses to infect new cells, thus providing the immune system greater opportunity to fight the infection.

In addition to investigating viruses of relevance to human health, PBI has recently extended its investigations of the antiviral efficacy of PBI-05204 against viruses of importance to commercial animal production as well. For example, Bovine viral diarrhea virus (BVDV), bovine respiratory syncytial virus (BRSV), bovine coronavirus (BCV), porcine influenza virus (PIV), porcine reproductive and respiratory syndrome virus (PRRSV), porcine coronavirus (PCV), and equine encephalitis virus (EEV) threaten the productivity of these animals worldwide. Development of therapeutics that can control the spread of these viruses is an unmet need. Oleandrin and PBI-05204 have been found to exhibit high therapeutic and prophylactic activity against those viruses even at extremely low concentrations. The company is currently working toward commercialization of related veterinary products for livestock and companion animals.