ArticlePLoS pathogens2021
Strategies to target SARS-CoV-2 entry and infection using dual mechanisms of inhibition by acidification inhibitors.
Article in PLoS pathogens, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT07254052 (Effectiveness of a Sustained-release Ammonium Chloride Formulation in Reducing the Viral Load of Patients With COVID-19 or Influenza), which is not on this map. Cited by 44 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Effectiveness of a Sustained-release Ammonium Chloride Formulation in Reducing the Viral Load of Patients With COVID-19 or Influenza
Who cites it
44 citing papers in PubMed, 69 citations in OpenAlex.
- Functional Specialization of Clathrin-Independent Endocytic Routes: Mechanisms and Cellular Roles.Traffic (Copenhagen, Denmark) · 2026Review
- A reversible broad-spectrum antiviral targets the human V-ATPase VResearch square · 2026Article
- Antiviral drug discovery and development: challenges and future directions.Signal transduction and targeted therapy · 2026Review
- Mycobacterium tuberculosis modulates phosphorylation of host ATP6V1E1 to promote intracellular survival.Nature communications · 2026Article
- Phosphoinositide kinase PIKfyve inhibitor apilimod blocks hepatitis E virus infection.eGastroenterology · 2026Article
- Inhibitory effect of [6]-shogaol against 3CLpro activity and SARS-CoV-2 infection.BMC complementary medicine and therapies · 2025Article
- UNC0638 inhibits SARS-CoV-2 entry by blocking cathepsin L maturation.Journal of virology · 2025Article
- Harnessing Nanohybridized Niclosamide for Precision Mpox Therapeutics.Advanced healthcare materials · 2025Review
- Cathepsins in cellular entry of human pathogenic viruses.Journal of virology · 2025Review
- Dynamin independent endocytosis is an alternative cell entry mechanism for multiple animal viruses.PLoS pathogens · 2024Article
- Identifications of novel host cell factors that interact with the receptor-binding domain of the SARS-CoV-2 spike protein.The Journal of biological chemistry · 2024Article
- Cholesterol and COVID-19-therapeutic opportunities at the host/virus interface during cell entry.Life science alliance · 2024Review
- Niclosamide, but not ivermectin, inhibits anoctamin 1 and 6 and attenuates inflammation of the respiratory tract.Pflugers Archiv : European journal of physiology · 2024Article
- The dynamin inhibitor, dynasore, prevents zoledronate-induced viability loss in human gingival fibroblasts by partially blocking zoledronate uptake and inhibiting endosomal acidification.Journal of applied oral science : revista FOB · 2024Article
- Alveolar-capillary endocytosis and trafficking in acute lung injury and acute respiratory distress syndrome.Frontiers in immunology · 2024Review
- Identification of diphenylurea derivatives as novel endocytosis inhibitors that demonstrate broad-spectrum activity against SARS-CoV-2 and influenza A virus both in vitro and in vivo.PLoS pathogens · 2023Article
- Mechanistic-Based Classification of Endocytosis-Related Inhibitors: Does It Aid in Assigning Drugs against SARS-CoV-2?Viruses · 2023Review
- Identification of niclosamide as a novel antiviral agent against porcine epidemic diarrhea virus infection by targeting viral internalization.Virologica Sinica · 2023Article
- Impact of various buffers and weak bases on lysosomal and intracellular pH: Implications for infectivity of SARS-CoV-2.FASEB bioAdvances · 2023Article
- CLIC and membrane wound repair pathways enable pandemic norovirus entry and infection.Nature communications · 2023Article
Corrections and comments
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Authors and funding
26 authors at 4 institutions in 1 country.
Funding
Abstract
Many viruses utilize the host endo-lysosomal network for infection. Tracing the endocytic itinerary of SARS-CoV-2 can provide insights into viral trafficking and aid in designing new therapeutic strategies. Here, we demonstrate that the receptor binding domain (RBD) of SARS-CoV-2 spike protein is internalized via the pH-dependent CLIC/GEEC (CG) endocytic pathway in human gastric-adenocarcinoma (AGS) cells expressing undetectable levels of ACE2. Ectopic expression of ACE2 (AGS-ACE2) results in RBD traffic via both CG and clathrin-mediated endocytosis. Endosomal acidification inhibitors like BafilomycinA1 and NH4Cl, which inhibit the CG pathway, reduce the uptake of RBD and impede Spike-pseudoviral infection in both AGS and AGS-ACE2 cells. The inhibition by BafilomycinA1 was found to be distinct from Chloroquine which neither affects RBD uptake nor alters endosomal pH, yet attenuates Spike-pseudovirus entry. By screening a subset of FDA-approved inhibitors for functionality similar to BafilomycinA1, we identified Niclosamide as a SARS-CoV-2 entry inhibitor. Further validation using a clinical isolate of SARS-CoV-2 in AGS-ACE2 and Vero cells confirmed its antiviral effect. We propose that Niclosamide, and other drugs which neutralize endosomal pH as well as inhibit the endocytic uptake, could provide broader applicability in subverting infection of viruses entering host cells via a pH-dependent endocytic pathway.
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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.