Compounds that inhibit the invasion of coronavirus in identified humans

SARS-CoV-2, the virus that causes COVID-19, attacks the body in multiple steps. Invading cells deep in the lungs, hijacking the mechanisms of human host cells and releasing a copy of itself are the two earliest steps, both of which are essential for viral infection.

In a new study published in the journal Science Advances, several existing compounds were found to be both the main protease (Mpro) and the lysosomal protease catepsin L, the major viral proteins required for SARS-CoV-2 replication in human cells. A human protein that is important for the virus to invade host cells.

“If we could develop compounds that shut down or significantly reduce both the invasion and replication processes, such double inhibition could increase the potency of these compounds in the treatment of coronavirus infections,” said the university. Associate Professor Yu Chen said. Of South Florida Health (USF Health) in the United States.

“Metaphorically, it’s like killing two birds with one stone,” said Chen, co-principal researcher of the study.

A team of researchers from the University of Arizona (UA) was built on previous studies that identified and analyzed several promising existing antiviral drugs as candidates for the treatment of COVID-19.

All candidates selected to pursue the target Mpro to block SARS-CoV-2 replication in human cells were raised in the laboratory.

The researchers said the two compounds, calpain inhibitors II and XII, were less active against Mpro in biochemical tests than another drug candidate called GC-376.

However, calpain inhibitors, especially XII, actually worked better than GC-376 in killing SARS-CoV-2 in cell culture, said Michael Sacco, the lead author of a doctoral student in Chen’s lab. Says.

“If these calpain inhibitors are not very effective in inhibiting the viral’s major proteases, they must be doing something else to explain their antiviral activity,” Sacco said. Said.

They found that calpain inhibitors are important human host proteases involved in mediating the invasion of SARS-CoV-2 from studies conducted by other groups, including UA collaborator and principal investigator Jun Wang. I learned that it can block other proteases, including the calpain L. cell.

In this latest study, researchers used advanced techniques, especially X-ray crystallography, to visualize how calpain inhibitors II and XII interact with the viral protein Mpro.

They observed that the calpain II inhibitor matched the target binding site on the surface of the SARS-CoV-2 main protease as expected.

They also found that calpain XII inhibitors adhered tightly to the active binding site of Mpro, adopting a unique configuration called the “reverse binding pose.”

The researchers said that the close fit optimizes the interaction of the inhibitor with the target viral protein and reduces the enzymatic activity that aids the growth of SARS-CoV-2.

“Our findings provide useful structural information on how we can design better inhibitors that target this important viral protein in the future,” Chen said.

In addition to the increased potency targeting both the viral protease Mpro and the human protease cathepsin L, or the desired drug effect at low doses, another advantage of the double inhibitor may be to suppress drug resistance. Said that.

“Therefore, double inhibitors make it more difficult to develop antiviral resistance because this type of compound remains effective against unchanged human host proteins as the viral protein changes. “Chen added.

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