ViroTreat, a novel integrative, regulatory network-based model for rapid identification of antiviral drugs has been validated by DarwinHealth scientists and their international colleagues. The team showed that 15 of the 18 drugs (83%) predicted to be effective induced significant reduction of SARS-CoV-2 replication, without affecting cell viability. In contrast, none of the 12 drugs selected as potential negative controls showed significant antiviral effect.
The model uses both computational and experimental assays to identify regulatory network aberrations induced by infecting viruses. It also can predict drugs capable of inhibiting viral replication and infectivity by stopping the hijacking of host cell regulatory mechanisms.
There is a huge need for antiviral drug discovery models that can predict, validate, and leverage the potential therapeutic effects of both established and investigational agents that inhibit viral replication.
In this study, drugs were prioritized for evaluation based on their context-specific mechanism of action determined by drug perturbations in appropriately matched cell lines. This model for host-directed pharmacological therapy, the researchers say, can be deployed to identify drugs targeting host cell-based master regulator signatures induced by virtually any pathogen. Master regulators are proteins whose activity is necessary and sufficient to maintain the transcriptional identity of a specific cellular phenotype.
The report was published in Communications Biology, and was compiled by scientists from the Department of Systems Biology, Columbia University, University of Florida, Molecular Virology at Heidelberg University, The Center for Precision Medicine at University of Bern, and DarwinHealth (New York), which conceived and led the project.
“The ViroTreat model we have developed can be seen as a chimeric method in which we specifically target the host with small molecules that render cells less permissive to viral infection and replication,” explained virologist Steeve Boulant, a lead author and Associate Professor, Department of Molecular Genetics & Microbiology, University of Florida College of Medicine.
He added that, “Importantly, recent progress in organoid culture models, which are functional ‘mini-organs in a dish,’ made it possible to secure physiologically actionable data in the setting of SARS-CoV-2 infection, thereby permitting us to deploy ViroTreat to quickly and predictably identify agents that reduce infectivity.
He added that, “These advances make it possible to study both new and existing viral pathogens, including influenza, in relevant organoid models in a matter of only a couple of months, thereby expanding our toolkit with a critical, new technology that will be invaluable for emerging pathogens, as well as for existing viral diseases for which better and safer treatments represent an unmet need.”
The application of single cell analysis to improve the precision of antiviral drug discovery was a key dimension of the model’s experimental design. “Because molecular analyses performed at the tissue level can easily produce distorted/mixed signals generated by both infected and non-infected cells, applying single-cell technology has been crucial for this work, explained lead author, Pasquale Laise, Senior Director of Single Cells Systems Pharmacology at DarwinHealth.
“In this model, single cell technology permitted us to clearly distinguish infected from non-infected cells, thereby uniquely amplifying the transcriptional effects of SARS-CoV-2 on infected host cells. This allowed our team to identify—in fact, quantify, using protein activity levels assessed by our proprietary VIPER algorithm—the specific Viral Checkpoint signature induced in the host by the virus; and, by extension, reliably predict drugs that would inhibit replication during the viral hijack phase of infection,” Laise added.
The DarwinHealth model, the researchers say, can identify and screen established pharmacologic therapies with low toxicity across a broad spectrum of mechanisms and viral pathogens—including coronaviruses and influenza—to identify host cell-directed therapies that may prove effective as either a direct, stand-alone intervention or as a complementary approach to direct antiviral treatments.