Targeting cathepsins: A potential link between COVID-19 and associated neurological manifestations

Many studies have shown that the lysosomal cathepsins, especially cathepsins B/L (CTSB/L) are required for SARS-CoV-2 entry into host cells. Lysosomal proteases, cathepsins are indispensable for normal health and are involved in several brain disorders occurring at different development age periods. On the other hand, it has been well known that COVID-19 infection is largely associated with several neurological disorders. Taken together these findings and given the high levels of expression of CTSB/L in the brain, we here proposed a reasonable hypothesis about the involvement of CTSB/L in the neurological manifestations linked to COVID-19. Pharmacological inhibitions of the CTSB/L could be a potential therapeutic target to block the virus entry as well as to mitigate the brain disorders. To this end, we utilized the network-based drug repurposing analyses to identify the possible drugs that can target CTSB/L. This study identifies the molecules like cyclosporine, phenytoin, and paclitaxel as potential drugs with binding ability to the CTSB/L. Further, we have performed molecular docking and all-atom molecular dynamics (MD) simulations to investigate the stability of CTSL-drug complexes. The results showed strong and stable binding of drugs with CTSL.

Automated summary

Lysosomal cathepsins, especially cathepsins B/L, play a crucial role in the entry of SARS-CoV-2 into host cells and may be involved in neurological manifestations linked to COVID-19. Through network-based drug repurposing analyses, cyclosporine, phenytoin, and paclitaxel were identified as potential drugs with binding ability to cathepsins B/L. Molecular docking and molecular dynamics simulations showed strong and stable binding of these drugs with cathepsins B/L.