What keeps most infectious disease researchers up at night aren’t infamous viruses like Ebola. Instead, influenza, commonly known as the flu, continues to be a clear and present danger to humanity. Influenza is a huge problem, as the virus sickens millions or kills thousands of people each year. A new pandemic along the lines of the 1918 Spanish flu has the potential to kill millions here and abroad. To that end, a team of collaborators have worked for years on broad-spectrum antiviral drugs developed from, of all things, banana plants. At present, although there are a number of antiinfluenza agents currently in phase II or III clinical trials, only three classes of drugs are approved to treat influenza virus infection in the United States: adamantanes, neuraminidase inhibitor Tamiflu and, as of October 2018, a new class with the sole member baloxavir, a viral endonuclease protein inhibitor. Adamantanes are now obsolete and Tamiflu is the practical option. Oseltamivir is associated with a moderate decrease in mortality among adults hospitalized for influenza, but it must be initiated within 48h of illness onset to be effective and only shortens the duration of symptoms by about one day in otherwise healthy adults.
Although oseltamivir resistance among circulating strains has generally been low since the emergence of the 2009 pandemic H1N1, resistance does occur and can be high in certain seasons. In a new paper published in the journal Proceedings of the National Academy of Sciences, Dr David Markovitz, MD, professor of Internal medicine in the Division of Infectious Diseases at Michigan Medicine and his team, have shown that an engineered compound based on a banana lectin, a protein called H84T, has real potential for clinical use against influenza. Lectins, or carbohydrate-binding proteins, have been proposed as potential antiviral agents due to their propensity to specifically bind the types of glycans present at high densities in glycoproteins on the surfaces of viruses. Indeed, influenza viruses are potential targets of lectins because they possess two major glycoproteins, hemagglutinin (HA) and NA, which mediate key steps of the viral life cycle In their experiments, more than 80% of mice exposed to a form of influenza that is typically fatal were able to survive the disease after receiving an injection of the protein, even up to 72 hours after exposure.
A downside of naturally occurring banana lectin, which can cause inflammation by inappropriately activating the immune system, wasn’t present in mice given H84T. Furthermore, because H84T is a protein, there was concern that the body would recognize it as foreign and develop antibodies against it, thereby neutralizing it or causing harm. The team found that while mice did develop antibodies against H84T, they didn’t appear to be adversely affected by them. The compound works because it targets a sugar called high mannose, which is present on the outside of certain viruses but not on most healthy cells. Scientists were able to show that H84T blocks the ability of the influenza virus to fuse with structures termed endosomes in the human cell, a key step in infection. Doing so disabled their ability to replicate and wreak havoc. Amazingly, this mechanism of action, binding of high mannose sugars on the surface of viruses, means that H84T is effective not only against influenza, but also against Ebola, HIV, measles, MERS (a new deadly viral illness that was first reported in Saudi Arabia in 2012), SARS and all other coronaviruses tested.
Indeed, a previous publication of 2010 by the same team proved that this lectin was effective in interfering with HIV replication. The team also provides early evidence that the compound is safe. Even more promising is that the compound works where Tamiflu has failed. Dr Markovitz’s team hopes to do more research with the compound in humans in the hopes of getting it to market: “We’ve also shown that there may be a synergistic effect between H84T and Tamiflu. We envision the government potentially stockpiling it in the event of a pandemic. However, there are many difficulties to commercialization. Pharmaceutical economics do not seem to favor the development of antivirals or antibacterials for one-time usage, which is a huge problem”.
- Edited by Dr. Gianfrancesco Cormaci, PhD; specialist in Clinical Biochemistry.
Covés-Datson EM et al., Markovitz DM. PNAS USA. 2020 Jan 13.
Covés-Datson EM et al. PLoS Negl Trop Dis. 2019; 13(7):e0007595.
Swanson MD et al., Markovitz DM. Cell. 2015 Oct; 163(3):746-58.