Discovery and evolution of 12N-substituted aloperine derivatives as anti-SARS-CoV-2 agents through targeting late entry stage

Compound 8a exhibited the promising activity against anti-SARS-CoV-2 via inhibiting host Cat B activity, and had the advantage of broad-spectrum anti-coronavirus and anti-cytokine activity in the treatment of COVID-19. [Display omitted] •54 aloperine derivatives were evaluated for the anti-SARS-CoV-2 activities.•Compound 8a exhibited the most promising activity against authentic SARS-CoV-2.•Compound 8a showed broad-spectrum anti-coronavirus and anti-cytokine effects.•Compound 8a displayed a good PK and safety profile in vivo.•Compound 8a blocked viral entry at a late stage by inhibiting host Cat B activity. So far, there is still no specific drug against COVID-19. Taking compound 1 with anti-EBOV activity as the lead, fifty-four 12N-substituted aloperine derivatives were synthesized and evaluated for the anti-SARS-CoV-2 activities using pseudotyped virus model. Among them, 8a exhibited the most potential effects against both pseudotyped and authentic SARS-CoV-2, as well as SARS-CoV and MERS-CoV, indicating a broad-spectrum anti-coronavirus profile. The mechanism study disclosed that 8a might block a late stage of viral entry, mainly via inhibiting host cathepsin B activity rather than directly targeting cathepsin B protein. Also, 8a could significantly reduce the release of multiple inflammatory cytokines in a time- and dose-dependent manner, such as IL-6, IL-1β, IL-8 and MCP-1, the major contributors to cytokine storm. Therefore, 8a is a promising agent with the advantages of broad-spectrum anti-coronavirus and anti-cytokine effects, thus worthy of further investigation.