Identifying COVID-19 Druggable Targets in the Lung, a Gateway for Viral Infection

Since the start of the global pandemic, Columbia University scientists from across all disciplines, including cancer research, have been hammering away to uncover the biology of the novel coronavirus, SARS-CoV-2, that leads to COVID-19. Wellington Cardoso, MD, PhD, professor of medicine in the Department of Medicine, Columbia’s Vagelos College of Physicians and Surgeons, and Andrea Califano, Dr, co-director of the Precision Oncology and Systems Biology research program at the Herbert Irving Comprehensive Cancer Center, are leading a new study focusing on the lungs—specifically the epithelium, or lining, of the lungs—to investigate potential druggable targets for COVID-19.

This fall, the research team received $600,000 in supplemental funding from the National Institute of Health for their collaboration.

While a number of COVID-19 studies have focused on the role SARS-CoV-2 plays in lung damage—sometimes leading to acute respiratory distress syndrome, or ARDS—less has been uncovered about the impact the novel coronavirus might have on the airway epithelium and its part in COVID-19.

“This represents a key gap in knowledge, given the accumulating evidence that airways are front-line targets of SARS-CoV-2 and may serve as high viral load SARS-CoV-2 reservoirs, responsible for making COVID-19 so highly contagious and transmittable,” says Dr. Cardoso, who also directs the Columbia Center for Human Development.

“By identifying druggable targets in the lung epithelium,” adds Dr. Califano, also chair of Columbia’s Department of Systems Biology, “we could stop COVID-19 dead in its tracks before it has a chance to damage the lungs, or worse, cripple a patient’s oxygen supply.”

The new research combines Dr. Cardoso’s expertise in biological mechanisms that drive lung development and pulmonary disease with Dr. Califano’s innovative computational frameworks that predict and identify master regulator proteins in cancer biology.

Most antiviral agents target virus-specific proteins and mechanisms of the host cell, say the researchers. In this work, Drs. Cardoso and Califano are instead targeting the host cell’s master regulator proteins, which control its hijacking and subsequent reprogramming, or replication, by the virus. According to them, a small module of master regulator proteins they call “ViroCheckpoint” is hijacked by the virus to use for its own replication and release.

The team intends to apply Dr. Califano’s computational method, called VIPER, to rapidly identify the master regulator proteins that mediate SARS-CoV-2’s hijacking of airway epithelial cells and to screen candidate drugs that may be able to reverse the virus’s effects. They will leverage established patient-derived airway epithelial culture systems developed by Dr. Cardoso’s lab as platforms for investigating this approach. Their method could lead to the development of novel antiviral therapy, either alone or in combination with existing treatments.

In preliminary studies in lung cancer cells infected with SARS-CoV (a less easily transmitted but more lethal coronavirus than SARS-CoV-2), the researchers identified potentially effective drugs using the VIPER (Virtual Inference of Protein activity by Enriched Regulon analysis) and OncoTreat algorithms developed by the Califano lab. The drugs indicated by ViroTreat, a virus-specific application of the OncoTreat algorithm used in oncology, were consistent with biological programs and pathways known to be affected by SARS-CoV.

The current studies will use a similar methodology in patient-derived airway cultures infected with SARS-CoV-2 developed by Dr. Cardoso’s lab. The team will identify cell type-specific signatures resulting from COVID-19 infection and screen a larger number of drugs, beyond those selected for oncological treatment. The investigators expect to identify three to six candidates, out of the top 10 experimentally validated OncoTreat-predicted drugs, for follow-up clinical trials.

If successful, this approach could be used in future pandemics, to develop treatments and/or vaccines in a fraction of the time it currently takes.