How DOE Scientists Disrupted COVID-19

Promising approaches

Usually, SARS-CoV-2 is spread by droplets suspended in the air of an infected person. Inside the body, the virus can quickly wreak havoc, invade healthy cells in multiple ways, reproduce, and trigger a variety of biological responses ranging from undetectable to mild to fatal. The United States has reported hundreds of thousands of COVID-19-related deaths and millions have died from the disease around the world.

“As we have seen, the virus is mutating. It’s the nature of viruses, especially in the real world in patients, ”Head said. “(Viruses are) constantly mutating and mutations that allow them to be more viable are increasing in importance around the world.”

“Tackling a virus requires a multi-pronged approach, both in terms of having this arsenal to respond to the evolution of the virus over time and also recognizing that trying to kill something that is not really alive is a very difficult task, ”she added. .

The molecular design team took shape, combining experimental validation and computation. Within months, they came up with five promising therapeutic approaches, each focusing on a unique aspect of the virus’s life cycle.

A promising therapy targets the spike protein, one of the oldest and most studied points of attack against the novel coronavirus. The spikes, which protrude from the outer layer of the virus, form a crown, giving the virus its name. The virus invades the cell when the spike protein binds to the human ACE2 receptor. The molecular design team used computer-designed antibodies to prevent the spike protein from binding to cells.

If the virus binds and then enters the cell, it can mature using two proteins – the main protease and the papain-like protease – necessary for viral replication. Possible drug therapy would block this activity to prevent the virus from maturing.

ORNL scientists have contributed to this potential solution with computer data and experiments. They have also contributed to the design, synthesis and testing specific to papain-like protease, an approach that is less studied but very promising. The team also characterized the major protease through world-class crystallography and X-ray and neutron experiments conducted by ORNL neutron scientists, as well as inhibitor synthesis experiments at ORNL’s CNMS. .

After entering the cell, maturing and replicating, the virus begins to spread throughout the body. The team is looking for small molecules that may turn into drugs that inhibit viral spread. Their results were shared with experimenters including Colleen Jonsson of the University of Tennessee and University of Chicago Health Sciences Center, both of whom have monitored biocontainment labs to test small molecules on live viruses.

An increase in viral load triggers the body’s immune response while the virus itself negatively impacts the immune response. The team is targeting ways to protect the body’s immune response by inhibiting papain-like protease, a key protein associated with the immune response. ORNL has designed new small molecules refined to prevent papain-like protease from allowing the novel coronavirus to replicate inside human cells.

In the final stage of viral replication, new spike proteins wrap around the viral RNA to create new copies of the virus. To inhibit this process, the team is studying ways to prevent the new virus from escaping infected cells.

Each approach, according to Head, is designed to interrupt a specific interaction between the SARS-CoV-2 virus and human cells. For maximum benefit in treating COVID-19, drug developers will likely pursue combination therapy to attack the virus on multiple fronts and reduce viral load.

Mice and drugs

The journey from scientific discovery to an approved and marketable drug is long and never guaranteed. But the promising first results from the DOE NVBL molecular design team justify the next step: a small study in mice.

“The DOE, of course, is not about developing drugs,” Head said. “We will put the information in the public domain so that others can take action on it. And our technology transfer office will engage with potential partners across the landscape. “

As of spring 2021, the team had data on six compounds worth exploring further, assuming they could all be converted to a form suitable for animal studies. Among the six, the team will select one for a collaborator to test for bioavailability in a mouse infected with SARS-CoV-2.

The world also began to emerge from the COVID-19 pandemic in the spring of 2021, as the vaccine became more widely available. But none of the molecular design team’s efforts have been in vain. In fact, Head and his colleagues are finding ways to expand the impact of their research after the NVBL (which was supposed to be a short-term venture) funding ended.

“We have relationships with several medical schools and medical centers that could potentially provide follow-up. And, we would probably also have conversations with the National Institutes of Health. There has to be this handover for somebody else to take it and move it on, ”Head said.

OLCF, SNS, HFIR and CNMS are facilities for users of the DOE Office of Science.

source: Oak Ridge National Laboratory

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