Houston, Texas, USA : Robert Davey, professor of microbiology at Boston University School of Medicine and researcher at Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL), in collaboration with researchers at Nagasaki University, Tokushima Bunri University, Kagoshima University, and Texas Biomedical Research Institute, have discovered that certain derivatives of amodiaquine, a medication typically used to treat malaria, could provide a new therapeutic approach to treating patients infected with Ebola.
From 2014-2016, an Ebola epidemic swept through West Africa, infecting more than 28,000 people and killing more than 11,000 in Guinea, Liberia, and Sierra Leone alone. The outbreak attracted the attention of virologists from around the world, and several of them, including Robert Davey, noticed something intriguing: patients with Ebola who had been treated with amodiaquine were 31 percent less likely to die.
“People were saying ‘it’s interesting’; I wondered if it was important,” says Davey. “I thought we should test some [chemical] derivatives and see if we could find some improvement over the amodiaquine performance.”
Davey and collaborators set out to learn exactly which parts of the amodiaquine molecule were inhibiting Ebola virus infection. Their findings, published in Antiviral Research, show that modified amodiaquine derivatives are significantly less toxic and nearly 10 times more effective at blocking Ebola virus than the original amodiaquine formula that greatly reduced mortality during the West Africa outbreak.
To make the discovery, Davey teamed up with other virologists on the hunt for new antiviral therapeutics. Serendipitously, one of Davey’s colleagues from Japan—Yasuteru Sakurai, from the National Research Center for the Control and Prevention of Infectious Diseases in Nagasaki—knew another Japanese researcher, Masanori Baba of Kagoshima University, who had already made a series of amodiaquine derivatives in an effort to find new treatments for HIV and other viruses.
Davey says amodiaquine inhibits the two diseases, malaria and Ebola virus disease, in related ways. All cells need to get food from their surroundings. With malaria, amodiaquine prevents the parasite from digesting food from inside red blood cells, so it basically starves to death. Ebola virus mimics food and tricks your cells into swallowing and trying to digest it. However, the virus senses this and uses it as a trigger to begin replication, avoiding digestion. So, by interfering with normal cell digestion, amodiaquine also blocks Ebola virus infection.
“With Ebola, we are affecting your own cell’s digestive system, but for a short time, which the cell can survive,” says Davey. “And the drugs that we developed likely improve targeting to places in the cell where Ebola virus likes to get to, whereas for malaria, the drugs are best at targeting the parasite’s feeding process which it needs all the time. It’s a subtle difference in chemistry, but it’s important for making an effective drug treatment for patients.”
Working together at Davey’s former lab in San Antonio, Texas, the team—which also included Masaaki Toyama of Kagoshima University and Norikazu Sakakibara of Tokushima Bunri University—tested nearly 70 amodiaquine derivatives, mixing each one with cells infected with Ebola virus and observing the effect that each derivative had on the live virus infection.
What they found, says Davey, was encouraging. Fourteen of the compounds tested did a better job inhibiting the Zaire strain of Ebola virus disease than straight amodiaquine. They also noticed that when two particular parts of the amodiaquine molecule were modified, the potency against the virus was further increased. Then, by combining the two features, they created further potent compounds, which appeared to completely prevent the virus from entering cells.
“If you combine those two things—less toxicity and better performance against the virus—you get something called a selective index,” says Davey. “The selective index that we found easily met the criteria for clinical development.”
Davey and BU researchers Manu Anantpadma and Patrick Keiser, are taking the next steps on the long road of developing the discovery from “it’s interesting” to an approved therapy. Next, Davey says, will come testing in animal models, as well as testing the potent compounds against other strains of Ebola virus.
Citation: Yasuteru Sakurai et al, Novel amodiaquine derivatives potently inhibit Ebola virus infection, Antiviral Research. DOI: 10.1016/j.antiviral.2018.10.025
Image : NEIDL researcher Robert Davey has found that derivatives from a commonly used anti-malarial can prevent Ebola virus from entering cells.
Image credit: Cydney Scott, Boston University Photography.
In a related study Texas Biomed scientists are researching Ebola-malaria connection.
Texas Biomed scientists researching Ebola-malaria connection
Ebola virus is a continuing threat in Central and West Africa, with an outbreak currently taking place in the Democratic Republic of Congo. The disease kills up to 90% of the people who get infected, and more than 150 people have died from Ebola so far this year. The factors that determine who is susceptible to Ebola infection and who is not are still a mystery.
Texas Biomed researchers—in collaboration with the University of Iowa—are trying to find out how malarial infections impact people exposed to Ebola virus. Both diseases are endemic in that region. “A significant number of people entering Ebola Virus Treatment Units during the 2014-2016 West African outbreak were infected with both the malarial parasites, Plasmodium falciparium, and Ebola virus. Our studies will assess these infections in an animal model to understand the molecular impact of malarial infection on the consequences of Ebola virus infections,” explained Professor Wendy Maury, Ph.D., the lead investigator at the University of Iowa.
“It has been postulated for some time now that malaria and Ebola virus co-infection has an effect on the outcome of Ebola virus disease,” Staff Scientist Olena Shtanko, Ph.D., said. “This is a really fascinating study which started in our lab this month.”
As part of a National Institutes of Health grant, Dr. Shtanko will be taking malaria-infected mice into the Biosafety Level 4 (BSL4) laboratory and challenging them with Ebola virus. The BSL4 lab is the highest safety rating for a biocontainment laboratory in order to house infectious agents for which there is no vaccine or cure.
The hypothesis of the Ebola-malaria connection under testing is that people with an acute (active and recent) malarial infection, where the immune response of the body is already ramped up, have a greater chance of surviving filovirus infection. If people have been infected with malaria but the infection is chronic, then they are more susceptible to Ebola.
Dr. Shtanko will begin with taking macrophages (large white blood cells that are part of the immune system) from infected mice and studying them to determine what role they may play in dual malaria/filovirus infection. From there, she will begin testing with the mice.
Knowing if this assertion is true might change how doctors design therapies for Ebola virus disease in areas where both diseases are present, perhaps paving the way for more tailored therapeutics. “It’s an area that needs to be addressed,” Shtanko stressed.
Other co-infections are known to impact each other’s outcome. For example, patients infected with HIV-1, a virus that causes AIDS, are more susceptible to tuberculosis infection.
Texas Biomed’s part in the “Mechanisms and consequences of Plasmodium/Ebola virus co-infections” study will be taking place over two years. The next step may involve testing in a higher-level animal model, such as nonhuman primates.
NIH explores connection between Ebola survival and co-infection with malaria parasites
People infected with Ebola virus were 20 percent more likely to survive if they were co-infected with malaria-causing Plasmodium parasites, according to data collected at an Ebola diagnostic laboratory in Liberia in 2014-15. Moreover, greater numbers of Plasmodium parasites correlated with increased rates of Ebola survival, according to a dozen collaborating research groups in the new study, published in Clinical Infectious Diseases. The survival difference was evident even after controlling for Ebola viral load and age. Scientists from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health (NIH), led the project.
At a joint diagnostic laboratory established in Liberia by NIH and the Centers for Disease Control and Prevention, the scientists tested 1,868 blood samples. The samples were from people seeking care for possible Ebola virus infection at the ELWA3 Ebola Treatment Unit in Monrovia. Testing confirmed Ebola virus infection in 1,182 samples; 956 of them were tested for Plasmodium parasites, and 185 were positive. Fifty-eight percent with both infections survived, compared to 46 percent who were infected with Ebola virus alone. Of the people with the highest Plasmodium levels, 83 percent survived.
Anti-malaria drugs were routinely administered to all patients seen at the Treatment Unit during the Ebola outbreak and had no bearing on the increased survival in Plasmodium-infected patients in the study, the researchers say. Moreover, in separate experiments conducted in the United States, treatment with antimalarials did not affect survival in laboratory mice infected with Ebola virus.
The research group is working to pinpoint a mechanism that could explain the association between Plasmodium infection and surviving an Ebola infection. If a connection is found, they say it might improve understanding of disease caused by Ebola and open possibilities for developing new treatments.
Citation: K Rosenke et al. Plasmodium parasitemia associated with increased survival in Ebola virus-infected patients. Clinical Infectious Diseases, DOI: 10.1093/cid/ciw452