Sumary of New strategy for designing COVID-19 antiviral drugs to inhibit key viral protein:
- Reviewed by Emily Henderson, B.Sc.Nov 9 2020 SARS-CoV-2, the respiratory virus that causes COVID-19, attacks the body in multiple steps..
- Gaining entry into cells deep within the lungs and hijacking the human host cell’s machinery to churn out copies of itself are two of the earliest steps — both essential for viral infection..
- A new study offers insight into designing antiviral drugs against COVID-19 by showing that some existing compounds can inhibit both the main protease (Mpro), a key viral protein required for SARS-CoV-2 replication 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 shut down or significantly reduce both processes – viral entry and viral replication – such dual inhibition may enhance the potency of these compounds in treating the coronavirus infection,”.
- All the candidates chosen to pursue target Mpro to block the replication of SARS-CoV-2 within human cells grown in the laboratory..
- However, the calpain inhibitors, especially XII, actually worked better than GC-376 at killing SARS-CoV-2 in cell cultures, said lead author Michael Sacco, a doctoral student in Dr. Chen’s laboratory..
- We figured if these calpain inhibitors were less effective at inhibiting the virus’s main protease, they must be doing something else to explain their antiviral activity..
- They learned from research done by other groups, including collaborator and study co-principal investigator Jun Wang, PhD, of UA, that calpain inhibitors can block other proteases, including cathepsin L, a critical human host protease involved in mediating SARS-CoV-2 entry into cells.”.
- Related Stories They observed that the calpain II inhibitor fit as expected into the targeted binding sites on the surface of the SARS-CoV-2 main protease..
- (A snug fit optimizes the inhibitor’s interaction with the targeted viral protein, decreasing the enzyme activity that helps SARS-CoV-2 proliferate.) “Our findings provide useful structural information on how we can design better inhibitors to target this key viral protein in the future,”.
- Besides the increased potency (desired drug effect at a lower dose) of targeting both viral protease Mpro and human protease cathepsin L, another benefit of dual inhibitors is their potential to suppress drug resistance, Dr…