ArticleCell discovery2022
Novel cleavage sites identified in SARS-CoV-2 spike protein reveal mechanism for cathepsin L-facilitated viral infection and treatment strategies.
Article in Cell discovery, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 102 citations in OpenAlex.
- Recent Advances in the Design of Inhibitors Targeting the Viral Entry and Replication of the SARS-CoV-2 Virus, Driven by In Silico Approaches.Molecules (Basel, Switzerland) · 2026Review
- The 100 K protein of adenovirus: character, location, and function.Archives of virology · 2026Review
- TMPRSS2-mediated coronavirus spike activation and inhibition.Nature structural & molecular biology · 2026Article
- CGM23 corresponds to a pan-coronavirus lipopeptide inhibitor potently inhibiting virion fusion.iScience · 2026Article
- Conformational bias in SARS-CoV-2 Spike CD4+ T-cell epitope dominance.Frontiers in immunology · 2026Article
- SARS-CoV-2 infection in hiPSC-derived neurons is cathepsin-dependent and causes differential accumulation of HIF1ɑ and phosphorylated tau.Molecular therapy. Nucleic acids · 2025Article
- Receptor affinity-selective differential dynamics of membrane fusion initiation govern deltacoronavirus cross-species transmission.Science China. Life sciences · 2025Article
- Effect of the S2' site cleavage on SARS-CoV-2 spike.Nature communications · 2025Article
- Molecular mechanisms of SARS-CoV-2 entry: implications for biomedical strategies.Microbiology and molecular biology reviews : MMBR · 2025Review
- Yeast-two-hybrid based high-throughput screening to discover SARS-CoV-2 fusion inhibitors by targeting the HR1/HR2 interaction.Acta pharmaceutica Sinica. B · 2025Article
- UNC0638 inhibits SARS-CoV-2 entry by blocking cathepsin L maturation.Journal of virology · 2025Article
- Peptidomimetic Phenoxymethyl Ketone Warheads as Potent Dual-Mode Inhibitors against SARS-CoV-2 MJournal of medicinal chemistry · 2025Article
- Syntaxin-6 restricts SARS-CoV-2 infection by facilitating virus trafficking to autophagosomes.Journal of virology · 2025Article
- Receptor Binding for the Entry Mechanisms of SARS-CoV-2: Insights from the Original Strain and Emerging Variants.Viruses · 2025Review
- SARS-related coronavirus S-protein structures reveal synergistic RBM interactions underpinning high-affinity human ACE2 binding.Science advances · 2025Article
- Delayed viral clearance and altered inflammatory responses affect severity of SARS-CoV-2 infection in aged mice.Immunity & ageing : I & A · 2025Article
- Host proteases: key regulators in viral infection and therapeutic targeting.Frontiers in immunology · 2025Review
- Phenotypic evolution of SARS-CoV-2 spike during the COVID-19 pandemic.Nature microbiology · 2025Article
- Molecular analysis of long COVID and new-onset diabetes mellitus: pathobiological relationships and current mechanistic views.Frontiers in endocrinology · 2025Review
- Immunogenicity of intranasal vaccine based on SARS-CoV-2 spike protein during primary and booster immunizations in mice.Human vaccines & immunotherapeutics · 2024Article
Corrections and comments
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Authors and funding
25 authors at 7 institutions in 1 country.
Funding
Abstract
The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important target for vaccine and drug development. However, the rapid emergence of variant strains with mutated S proteins has rendered many treatments ineffective. Cleavage of the S protein by host proteases is essential for viral infection. Here, we discovered that the S protein contains two previously unidentified Cathepsin L (CTSL) cleavage sites (CS-1 and CS-2). Both sites are highly conserved among all known SARS-CoV-2 variants. Our structural studies revealed that CTSL cleavage promoted S to adopt receptor-binding domain (RBD) "up" activated conformations, facilitating receptor-binding and membrane fusion. We confirmed that CTSL cleavage is essential during infection of all emerged SARS-CoV-2 variants (including the recently emerged Omicron variant) by pseudovirus (PsV) infection experiment. Furthermore, we found CTSL-specific inhibitors not only blocked infection of PsV/live virus in cells but also reduced live virus infection of ex vivo lung tissues of both human donors and human ACE2-transgenic mice. Finally, we showed that two CTSL-specific inhibitors exhibited excellent In vivo effects to prevent live virus infection in human ACE2-transgenic mice. Our work demonstrated that inhibition of CTSL cleavage of SARS-CoV-2 S protein is a promising approach for the development of future mutation-resistant therapy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.