The University of Maryland School of Medicine (UMSOM) researchers have identified the most toxic proteins made by SARS-COV-2 and then used an FDA-approved cancer drug to blunt the viral protein’s detrimental effects.
In experiments in fruit flies and human cell lines, the team discovered the cell process that the virus hijacks, illuminating new potential candidate drugs that could be tested for treating severe Covid-19 disease patients. The findings were published in two studies simultaneously in Cell & Bioscience, a Springer Nature journal.
“Our work suggests there is a way to prevent SARS-COV-2 from injuring the body’s tissues and doing extensive damage,” said senior author of the study Zhe “Zion” Han, PhD, Associate Professor of Medicine and Director of the Centre for Precision Disease Modelling at UMSOM. He notes that the most effective drug against Covid-19, remdesivir, only prevents the virus from making more copies of itself, but it does not protect already infected cells from damage caused by the viral proteins.
SARS-COV-2 infects cells and hijacks them into making proteins from each of its 27 genes. Dr. Han’s team introduced each of these 27 SARS-CoV-2 genes in human cells and examined their toxicity. They also generated 12 fruit fly lines to express SARS-CoV-2 proteins likely to cause toxicity based on their structure and predicted function.
The researchers found that a viral protein, known as Orf6, was the most toxic, killing about half of the human cells. Two other proteins (Nsp6 and Orf7a) also proved toxic, killing roughly 30-40% of the human cells. Fruit flies that made any one of these three toxic viral proteins in their bodies were less likely to survive to adulthood. Those fruit flies that did live had problems like fewer branches in their lungs or fewer energy-generating power factories in their muscle cells.
The team then discovered that one of these human moving proteins, targeted by the virus, gets blocked by the cancer drug selinexor. The researchers tested selinexor on human cells and fruit flies making the toxic viral protein to see if the drug could help reverse the damage. Selinexor, like many cancer drugs is itself toxic. However, after accounting for its toxic effects, the drug improved human cell survival by about 12%. Selinexor prevented early death in about 15% of the flies making the toxic viral protein. The drug also restored branches in the lungs and the energy-generators in the muscle cells. Selinexor is FDA-approved to treat certain blood cancers.
“More than 1,000 FDA-approved drugs are in clinical trials to test as treatments for Covid-19, and luckily a trial testing selinexor, the drug used in our study, is being performed already,” said Dr. Han. “If this trial proves to be successful, our data will have demonstrated the underlying mechanism for why the drug works.”
Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, University of Maryland Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine, said: “Although we now have vaccines, it may still be a while before we will have Covid-19 infections under control, especially with the new variants emerging. We will need to tap into every tool in the arsenal available to protect people from needless sickness, disability or even death, and this study guides us towards a new target for potential therapeutics.”