ArticlePLoS computational biology2020
Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARS-CoV-2 infection.
Article in PLoS computational biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 95 papers.
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Who cites it
95 citing papers in PubMed, 147 citations in OpenAlex.
- Nicotine and cotinine enhance SARS-CoV-2 entry through distinct but complementary mechanisms in human respiratory epithelial cells.Journal of virology · 2026Article
- CGM23 corresponds to a pan-coronavirus lipopeptide inhibitor potently inhibiting virion fusion.iScience · 2026Article
- Model-informed prediction of antiviral drug combination synergy from sparse data using complementary mechanistic and pharmacodynamic approaches.Frontiers in pharmacology · 2026Article
- SARS-CoV-2 Evolution in Humans Enables Its Transmission to Nonhuman Primates.Molecular biology and evolution · 2025Article
- Anti-Oxidant, Anti-Inflammatory and Antiviral Properties of Luteolin Against SARS-CoV-2: Based on Network Pharmacology.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Cathepsin B deficiency disrupts cortical development via PEG3, leading to depression-like behavior.Communications biology · 2025Article
- UNC0638 inhibits SARS-CoV-2 entry by blocking cathepsin L maturation.Journal of virology · 2025Article
- A Systematic Review of Case Reports of New-Onset Atrial Fibrillation in COVID-19 Patients.Cureus · 2025Review
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- Risk impact of SARS-CoV-2 coronavirus and spike protein on cardiac tissue: a comprehensive review.Physiological research · 2024Review
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- A novel multitargeted self-assembling peptide-siRNA complex for simultaneous inhibition of SARS-CoV-2-host cell interaction and replication.Molecular therapy. Nucleic acids · 2024Article
- Potential Effects of Hyperglycemia on SARS-CoV-2 Entry Mechanisms in Pancreatic Beta Cells.Viruses · 2024Review
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- GeneRaMeN enables integration, comparison, and meta-analysis of multiple ranked gene lists to identify consensus, unique, and correlated genes.Briefings in bioinformatics · 2024Article
- Cleavage of the syncytial protein of J paramyxovirus is required for its ability to promote cell-cell fusion.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- TMPRSS2-mediated SARS-CoV-2 uptake boosts innate immune activation, enhances cytopathology, and drives convergent virus evolution.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Risk factors for severe COVID-19 disease increase SARS-CoV-2 infectivity of endothelial cells and pericytes.Open biology · 2024Article
- Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry.Nature communications · 2023Article
- Global asymptotic stability of a delay differential equation model for SARS-CoV-2 virus infection mediated by ACE2 receptor protein.Applied mathematics letters · 2023Article
35 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
Abstract
The entry of SARS-CoV-2 into target cells requires the activation of its surface spike protein, S, by host proteases. The host serine protease TMPRSS2 and cysteine proteases Cathepsin B/L can activate S, making two independent entry pathways accessible to SARS-CoV-2. Blocking the proteases prevents SARS-CoV-2 entry in vitro. This blockade may be achieved in vivo through 'repurposing' drugs, a potential treatment option for COVID-19 that is now in clinical trials. Here, we found, surprisingly, that drugs targeting the two pathways, although independent, could display strong synergy in blocking virus entry. We predicted this synergy first using a mathematical model of SARS-CoV-2 entry and dynamics in vitro. The model considered the two pathways explicitly, let the entry efficiency through a pathway depend on the corresponding protease expression level, which varied across cells, and let inhibitors compromise the efficiency in a dose-dependent manner. The synergy predicted was novel and arose from effects of the drugs at both the single cell and the cell population levels. Validating our predictions, available in vitro data on SARS-CoV-2 and SARS-CoV entry displayed this synergy. Further, analysing the data using our model, we estimated the relative usage of the two pathways and found it to vary widely across cell lines, suggesting that targeting both pathways in vivo may be important and synergistic given the broad tissue tropism of SARS-CoV-2. Our findings provide insights into SARS-CoV-2 entry into target cells and may help improve the deployability of drug combinations targeting host proteases required for the entry.
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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.