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Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available, their efficacy on emerging coronaviruses in the future, including SARS-CoV-2 variants, might be compromised. Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses. Cathepsin L (CTSL) and calpain-1 (CAPN1) are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response. Here, two peptidomimetic \u03b1-ketoamide compounds, <jats:bold>14a<\/jats:bold> and <jats:bold>14b<\/jats:bold>, were identified as potent dual target inhibitors against CTSL and CAPN1. The X-ray crystal structures of human CTSL and CAPN1 in complex with <jats:bold>14a<\/jats:bold> and <jats:bold>14b<\/jats:bold> revealed the covalent binding of \u03b1-ketoamide groups of <jats:bold>14a<\/jats:bold> and <jats:bold>14b<\/jats:bold> to C25 of CTSL and C115 of CAPN1. Both showed potent and broad-spectrum anticoronaviral activities in vitro, and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern (VOCs) with EC<jats:sub>50<\/jats:sub> values ranging from 0.80 to 161.7\u2009nM in various cells. Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance. Moreover, <jats:bold>14a<\/jats:bold> and <jats:bold>14b<\/jats:bold> exhibited good oral pharmacokinetic properties in mice, rats and dogs, and favorable safety in mice. In addition, both <jats:bold>14a<\/jats:bold> and <jats:bold>14b<\/jats:bold> treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse model. And <jats:bold>14b<\/jats:bold> also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%. Further evaluation showed that <jats:bold>14a<\/jats:bold> and <jats:bold>14b<\/jats:bold> exhibited excellent anti-inflammatory effects in Raw 264.7 mouse macrophages and in mice with acute pneumonia. Taken together, these results suggested that <jats:bold>14a<\/jats:bold> and <jats:bold>14b<\/jats:bold> are promising drug candidates, providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.<\/jats:p>","DOI":"10.1038\/s41392-024-01758-8","type":"journal-article","created":{"date-parts":[[2024,3,6]],"date-time":"2024-03-06T00:02:05Z","timestamp":1709683325000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and 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