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Computer-based screen identifies new antiviral targets for existing drugs
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Donald H. Rubin
Researchers developed a computer-based screening method that has identified 110 new antiviral targets for current drugs, according to recent findings published in PLoS Computational Biology.
“The prospect of drug repositioning (finding new indications for existing FDA-approved drugs) is emerging as a promising alternative to traditional drug design and offers an improved risk-benefit trade-off in combating infectious diseases,” Donald H. Rubin, MD, professor of medicine, microbiology and immunology at Vanderbilt University School of Medicine, and colleagues wrote. “We have demonstrated the use of a computable representation of genetic testing to effectively identify new potential antiviral indications for existing drugs.”
Gene-trap insertional mutagenesis is a high-throughput method that randomly disrupts host genes, the investigators wrote. Through this disruption, researchers can discover which genes are both essential for viral replication and nonessential for host cell survival. The proteins produced by the discovered genes, therefore, would make for good drug targets.
Rubin and colleagues used gene-trap insertional mutagenesis to identify more than 700 candidate host genes that mediated the cytotoxic effects of cowpox, Ebola, HIV, herpes simplex, Marburg virus, polio, reovirus, rhinovirus-2 and rhinovirus-16 as well as Francisella tularensis and five toxins. Afterward, the researchers developed a systems biology-based pipeline to characterize the candidate targets through networking and bioinformatics analysis.
By incorporating the drug-gene signatures from a connectivity map into a virus-host interactome, the researchers identified 110 antiviral drug targets. For example, they found 16 drugs with anti-HIV-1 indication potential. Among the top five anti-HIV agents, four had been validated in previous studies. Seven drugs showed anti-Ebola indication potential, including ajmaline, ricinine, clopamide, piroxicam and danazol. The researchers wrote that targeting MERTK, CTSB, TYRO3 and FURIN with alkaloid ajmaline “may provide a new therapeutic strategy against Ebola virus.”
Figure 1. A computer-based screening method could reveal the virus-fighting potential of drugs initially developed to treat other conditions.
Source: Isabel Odriozola, Flickr.
In addition, Rubin and colleagues learned that poliovirus receptor-like 3 is necessary for Clostridium difficile TcdB-induced cytotoxicity. They also validated RAB9 and ADAM10 as two important genes for viral replication, and they identified multiple cancer-related genes as being important in viral replication.
“Although antiviral drug-discovery approaches have yielded notable successes in recent years, in many cases (such as with Ebola virus) no small molecular drugs are available to combat infection,” the researchers wrote. “However, a systems biology-based antiviral drug repositioning, establishing the identification of new antiviral indications for existing drugs, will undoubtedly have a significant impact in antiviral drug discovery and expedite drug development.” – by Will Offit
Disclosure: One researcher reports being previously employed by Zirus and being currently employed by GeneTag Technology.
Perspective
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Sten H. Vermund
The Rubin lab has been involved in a long-term discovery process to find mammalian genes essential for the replication of many important viruses, or that mediate the pathological effects of bacterial toxins.
By integrating gene-trap insertional mutagenesis and systems-biology analysis, the VA-Vanderbilt team identified 110 putative drug-susceptible antiviral targets and prioritized several existing drugs that have antiviral potential.
An exciting element of this study is the successful use of a computable representation of genetic testing to effectively identify new potential antiviral indications for existing drugs. This innovation can expedite translational processes with different complex diseases, particularly drug development.
Disclosure: Vermund reports no relevant financial disclosures.
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