SARS-CoV-2, the virus that causes COVID-19, attacks the body in several stages. (File)
New Delhi:
U.S. scientists have identified some existing compounds that can inhibit two key proteins required by the new coronavirus to enter human cells and reproduce, a breakthrough that could help develop new antiviral drugs effective for COVID-19.
SARS-CoV-2, the virus that causes COVID-19, attacks the body in several stages. Getting into cells deep in the lungs and hijacking the human host cell’s machinery to make copies of itself are two of the first steps – both essential for viral infection.
The new study, published in the journal Science Advances, found that certain existing compounds can inhibit both the major protease (Mpro), a key viral protein necessary for the replication of SARS-CoV-2 inside human cells. , and the lysosomal protease cathepsin L, a human protein important for viral entry into host cells.
“If we can develop compounds to stop or significantly reduce both processes – viral entry and viral replication – such a double inhibition could enhance the potency of these compounds in the treatment of coronavirus infection,” said Yu Chen , associate professor at the University. of South Florida Health (USF Health) in the United States.
“Metaphorically, it’s like killing two birds with one stone,” said Yu Chen, co-principal investigator of the study.
The team, including researchers at the University of Arizona (UA), built on their previous work, which identified and analyzed several promising and existing antiviral drugs as candidates to treat COVID-19.
All of the candidates chosen to pursue the Mpro target to block SARS-CoV-2 replication in human cells were cultured in the laboratory.
Two of the compounds, calpain II and XII inhibitors, did not show as much activity against Mpro as another drug candidate called GC-376 in biochemical tests, the researchers said.
However, calpain inhibitors, especially XII, actually worked better than GC-376 in killing SARS-CoV-2 in cell cultures, said lead author Michael Sacco, a doctoral student in the Yu Chen’s laboratory.
“We figured that if these calpain inhibitors were less effective at inhibiting the main protease of the virus, they needed to do something else to explain their antiviral activity,” Sacco said.
They learned from research by other groups, including collaborators and study co-principal investigator Jun Wang of UA, that calpain inhibitors can block other proteases, including cathepsin L. , a critical human host protease involved in mediating entry of SARS-CoV-2 into cells.
In this latest study, the researchers used advanced techniques, in particular X-ray crystallography, to visualize how calpain II and XII inhibitors interacted with the viral protein Mpro.
They observed that the calpain II inhibitor adapted as expected in targeted binding sites on the surface of the main protease of SARS-CoV-2.
They also found that the calpain XII inhibitor adopted a unique configuration – called “reverse binding pose” – to closely match the active binding sites of Mpro.
A tight fit optimizes the inhibitor’s interaction with the targeted viral protein, decreasing the enzyme activity that helps SARS-CoV-2 proliferate, the researchers said.
“Our results provide useful structural information on how we can design better inhibitors to target this key viral protein in the future,” said Yu Chen.
He noted that in addition to the increased potency, or desired drug effect at a lower dose, targeting both the viral protease Mpro and the human protease cathepsin L, another advantage of dual inhibitors is their potential to suppress drug resistance.
“Thus, a double inhibitor makes it more difficult to develop resistance to antivirals, because even if the viral protein changes, this type of compound remains effective against the human host protein which has not changed,” added Yu Chen.
