Decoding COVID-19's Achilles' heel to inspire new treatments

As the highly infectious novel coronavirus continues to spread, scientists are looking for new ways to kill the virus. While Gilead Sciences’ repurposed antiviral remdesivir has shown activity against COVID-19, its clinical benefits may be limited, creating a demand for better treatments.

Now, Ernesto Estrada at the University of Zaragoza in Spain has found what could be the Achilles’ heel of SARS-CoV-2, the virus that causes COVID-19. It's a protein that’s essential for the reproduction of the virus, making it an excellent target for potential drugs, he believes.

The protein is called main protease (Mpro). It's an enzyme that cuts precursor molecules that are translated from viral RNA to make functional viral proteins. Proteases are attractive drug targets because of their vital role in viral replication.

In a new study published in the journal Chaos, Estrada showed that the main protease of SARS-CoV-2 is a lot more sensitive to small disturbances than that of the SARS coronavirus that led to a previous outbreak in the early 2000s. Founded in 1991, Chaos is published by the American Institute of Physics and focuses on multiple disciplines related to nonlinear science.

A team led by the University of Lübeck in Germany recently used high-intensity X-ray light to paint the 3D structure of SARS-CoV-2’s main protease. They found that SARS-CoV-2 and SARS-CoV share 96% of their amino acid sequence, with differences at just 12 out of 303 positions. Estrada wondered whether such similarities are also reflected in "topological" features, such as how the two coronaviruses’ proteases change in response to outside forces such as twisting and stretching.

Estrada set out to answer that question by looking at Mpro as a theoretic network, or a simplified model of the 3D structure of the protein. “They’re called protein residue networks, where we represent every amino acid as a node, and the interaction between two amino acids is represented by a link between the two,” he explained in a statement.

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Turns out, while the topological characteristics of the two networks are indeed similar, the transmission of information is not. In fact, SARS-CoV-2's Mpro is 1,900% more sensitive than SARS-CoV Mpro in transmitting tiny structural changes across the whole network, Estrada reported.

One amino acid that has increased dramatically in its sensitivity to transmission of information in SARS-CoV-2's Mpro is Cys-145, which just happens to be a catalytic site critical to the enzyme’s function. It is also involved in binding with inhibitors.

Scrutinizing the genetic forces at work in the spread of SARS-CoV-2 is now a priority of researchers around the world, who are stepping up with a variety of ideas for thwarting the virus. Bioengineers at Stanford University, for example, found that a CRISPR system could be deployed to inhibit 90% of coronaviruses, including SARS-CoV-2, by disrupting their genetic code. 

The University of Zaragoza team sees value in identifying the roles of specific amino acids in SARS-CoV-2's Mpro. The researchers believe their technique could be used to screen drug candidates to identify treatments that can inhibit the main protease of the virus, Estrada said.