A potential broad spectrum antiviral
Posted by ycpmicro
Nick Altland (Spring 2010 Micro) wrote to me via FB: “Have you heard of this?” The link describes a press release from labs at MIT, and detailing research published in the medical journal PLoSONE. The findings describe a possible way of exploiting the reproduction of viruses at a level that spans different viral groups, and suggests a novel approach to viral therapy. Viral reproduction is intricately tied to the host cell reproduction, and therefore drugs that might inhibit the transcription of viral genes or the replication of viral genomes would also likely have significant effects on these processes in the host cell as well. Many antivirals which target these basic cellular processes have significant side effects as result. Some antivirals target specific aspects of the virus life cycle. Tamiflu for instance blocks the activity of the enzyme neuraminidase, which the virus needs in order to release new viral particles from an infected cell. Resistance occurs when the highly variable neuraminidase gene mutates, and this occurs at a high frequency. Because neuraminidase is an enzyme only found in influenza virus, the drug Tamiflu only has effects with this disease.
The research out of MIT has worked to identify a process that is basic to all virus reproduction and not found in normal cells. This would potentially allow them to target virally-infected cells while leaving uninfected cells alone. The premise draws from an analysis of the action of interferons. Interferons are signalling molecules that are released by the innate immune system during viral infections, and enable our cells to partially resist the effects of viruses. Viral infections are recognized by the presence of double stranded RNA (dsRNA) molecules in virally infected cells, and one response to this is a triggering of programmed cell death or apoptosis. Apoptosis eliminates infected cells before viral reproduction can be completed. dsRNAs arise in many virally infected cells, regardless of the type of viral genome, so the presence of these types of nucleic acids is a common feature of virus infection.
The potential for therapy comes from this; the researchers engineered a novel molecule they have called DRACO, for Double-stranded RNA (dsRNA)Activated Caspase Oligomerizer. DRACOs combine a sensitive method for detecting dsRNA with a potent effector of apoptosis. When DRACOs were mixed with tissue culture cells, the proteins rapidly entered into cells and persisted in the cells for several days. In tissue culture cells that previously contained dsRNA, apoptosis was rapidly induced when DRACOs were introduced, resulting in death of those cells. Control tissue culture cells were unaffected. Apoptosis inducing effects were noted with a variety of virally infected tissue culture cells, including infections due to rhinovirus, influenza virus, dengue virus, adenovirus, and reovirus. In adult mice challenged with influenza virus, DRACOs offered protection when administered concurrently with the virus, with no obvious toxicity issues in any target organs.
Future directions for the research will be at optimizing the in vivo delivery of DRACOs, in order to maximize their effectiveness without bringing too much cell death, particularly in a chronic viral infection. Additionally, it is not clear what the response of viral population would be to this method of therapy, and whether resistance would arise over time.
About ycpmicroMy name is David Singleton, and I am an Associate Professor of Microbiology at York College of Pennsylvania. My main course is BIO230, a course taken by allied-health students at YCP. Views on this site are my own.
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