Scientists in the San Antonio-based Texas Biomedical Research Institute Department of Immunology and Virology have discovered a promising drug therapy candidate that acts on the process by which Ebola virus infects healthy cells. The researchers’ findings are published in the February 27, 2015 edition of the journal Science.
Dr. Robert Davey, Ewing Halsell Scholar at Texas Biomedical Research Institute (TBRI) and his team of researchers report that a small molecule called Tetrandrine derived from an Asian herb has been identified as active in both inhibition of human white blood cell infection with Ebola in both in vitro and petri dish experiments and has also been demonstrated to prevent Ebola virus disease infections in mice.
The current worst-on-record Ebola virus disease outbreak centered in West Africa has killed more than 8,600 people worldwide, creating an international public health crisis that proved to be dishearteningly tenacious. The disease, which causes hemorrhagic fever in humans and for which there is currently no approved therapy or preventative vaccine, continues to infect thousands in West Africa.
Scientists have been working with the Ebola virus at Texas Biomed in the Institute’s Biosafety Level 4 containment laboratory for more than a decade in hope of finding a vaccine, therapies and early detection methods for the virus. Dr. Davey and his team have conducted research for more than five years toward the objective of identifying and pinpointing Ebola virus disease therapy targets. The Davey Lab’s research has been mainly focused on finding ways to arrest the virus before it has the opportunity to invade cells or interact with cellular factors, which would constitute a critical first step in combatting the spread of infection.
Collaborators and Co-authors on the Science paper describing the work achieved at Texas Biomed by Dr. Davey and his colleagues, entitled “Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment“ (Science 27 February 2015: Vol. 347 no. 6225 pp. 995-998 DOI: 10.1126/science.1258758) include Robert A. Davey and Yasuteru Sakurai of the Texas Biomedical Research Institute, San Antonio, Texas; Andrey A. Kolokoltsov of the University of Texas Medical Branch at Galveston; Cheng-Chang Chen, Christian Grimm, Christian Wahl-Schott, and Martin Biel of the Center for Integrated Protein Science Munich (CIPSM) at the Department of PharmacyCenter for Drug Research at Ludwig-Maximilians-Universittät München, in Munich, Germany who did special cell analysis; Michael W. Tidwell and William E. Bauta of the Southwest Research Institute at San Antonio; Norbert Klugbauer of the Institute for Experimental and Clinical Pharmacology and Toxicology at Albert-Ludwigs-Universität Freiburg at Freiburg, Germany.
In their study they found that entry of the Ebola virus into host cells is via the endosomal calcium channels called two-pore channels (TPCs).
Having been able to demonstrate the critical role played by two pore channels in Ebola virus infection, a mechanism not previously observed with any other virus, Dr. Davey’s team also showed how drugs that target this particular interaction show some promise as potential Ebola virus disease treatments. The team determined that drugs currently being used to lower high blood pressure (hypertension) also have the ability to turn this key calcium sensor on and off. Disrupting TPC function by gene knockout, small interfering RNAs, or small-molecule inhibitors halted virus trafficking and prevented infection.
Working with the collaborators in Munich, Germany and at the Southwest Research Institute, the Davey team tested several small molecules to see which was most effective at turning the sensors off, prohibiting Ebola virus from moving any further through the cell. The Asian herbal-derived molecule Tetrandrine was found to be the most potent small molecule the researchers tested, and was shown to inhibit infection of human macrophages that are the Ebola virus’s primary target in vivo. Tetrandrine was also shown to have therapeutic efficacy in mice, leading the scientists to deduce that TPC proteins play a key role in Ebola virus infection and are potentially effective targets for antiviral therapy.
Referencing previous studies, Dr. Davey observes that during this process, he knew that calcium signaling within cells, which allows them to transmit electrical charges to each other, also controls many cell processes and played a prominent role in Ebola virus infection.
“We were not able, however, to pinpoint the mechanisms involved in this process,” Dr. Davey explains. “With this research, we discovered that two pore channels (TPCs) are the key calcium sensor involved in Ebola virus infection. These TPCs essentially need to be turned on in order for the virus to function properly.”
Dr. Davey compares the function of TPCs to those of traffic cops and air conditioners, in that they help direct the endosomes and any virus it may be carrying through the cell, while making the endosomes and any passengers more comfortable during the journey.
The team found that Tetrandrine also protected mice from infection without obvious side effects, and in addition to being the most potent compound tested, showed little evidence of cytotoxicity and required a smaller doses to be effective and well-tolerated.
“When we tested in mice, the drugs stopped virus replication and saved most of them from disease,” Dr. Davey notes. “Essentially, this drug shows an ability to stop the virus before it has a chance interact with cellular factors, thus stopping the virus from continuing its infection process.”
“We are very excited about the progress made in this study and the momentum it provides as scientists across the world vigorously search for effective vaccines and treatments against Ebola virus… We are cautiously optimistic,” Dr.Davey concludes. “The next step in the process is to test both safety and effectiveness of the interaction of the drug with Ebola virus in non-human primates.”
Texas Biomed, formerly the Southwest Foundation for Biomedical Research, is a leading independent biomedical research institution dedicated to advancing health worldwide through innovative biomedical research. Located on a 200-acre campus on the northwest side of San Antonio, Texas, the Institute partners with hundreds of researchers and institutions around the world to develop vaccines and therapeutics against viral pathogens causing AIDS, hepatitis, herpes, hemorrhagic fevers and parasitic diseases responsible for malaria, schistosomiasis and Chagas disease. The Institute also has programs in the genetics of cardiovascular disease, diabetes, obesity, psychiatric disorders and other diseases. For more information on Texas Biomed, visit:
Texas Biomedical Research Institute
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