Strategies to target SARS-CoV-2 entry and infection using dual mechanisms of inhibition by acidification inhibitors

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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 NH ₄Cl, 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.

Author summary

This study investigates the cellular mechanisms by which SARS-CoV-2 can gain entry into human cells. We find that the virus employs diverse endocytic processes to enter cells and the acidic environment within these endocytic compartments is essential for infection. Using these observations from first principles, we screened a small set of FDA-approved drugs which could potentially inhibit endosomal acidification and therefore prevent viral entry and infection. The routinely prescribed anti-helminthic drug, Niclosamide, was observed to have this capability. Our study proposes that drugs altering both endocytic entry as well as endosomal acidification can assist in the clinical management of viral infections.

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Most cited references 95

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A Novel Coronavirus from Patients with Pneumonia in China, 2019

Na Zhu, Dingyu Zhang, Wenling Wang … (2020)

Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)

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SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)

Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

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Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Manli Wang, Ruiyuan Cao, Leike Zhang … (2020)

Dear Editor, In December 2019, a novel pneumonia caused by a previously unknown pathogen emerged in Wuhan, a city of 11 million people in central China. The initial cases were linked to exposures in a seafood market in Wuhan. 1 As of January 27, 2020, the Chinese authorities reported 2835 confirmed cases in mainland China, including 81 deaths. Additionally, 19 confirmed cases were identified in Hong Kong, Macao and Taiwan, and 39 imported cases were identified in Thailand, Japan, South Korea, United States, Vietnam, Singapore, Nepal, France, Australia and Canada. The pathogen was soon identified as a novel coronavirus (2019-nCoV), which is closely related to sever acute respiratory syndrome CoV (SARS-CoV). 2 Currently, there is no specific treatment against the new virus. Therefore, identifying effective antiviral agents to combat the disease is urgently needed. An efficient approach to drug discovery is to test whether the existing antiviral drugs are effective in treating related viral infections. The 2019-nCoV belongs to Betacoronavirus which also contains SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV). Several drugs, such as ribavirin, interferon, lopinavir-ritonavir, corticosteroids, have been used in patients with SARS or MERS, although the efficacy of some drugs remains controversial. 3 In this study, we evaluated the antiviral efficiency of five FAD-approved drugs including ribavirin, penciclovir, nitazoxanide, nafamostat, chloroquine and two well-known broad-spectrum antiviral drugs remdesivir (GS-5734) and favipiravir (T-705) against a clinical isolate of 2019-nCoV in vitro. Standard assays were carried out to measure the effects of these compounds on the cytotoxicity, virus yield and infection rates of 2019-nCoVs. Firstly, the cytotoxicity of the candidate compounds in Vero E6 cells (ATCC-1586) was determined by the CCK8 assay. Then, Vero E6 cells were infected with nCoV-2019BetaCoV/Wuhan/WIV04/2019 2 at a multiplicity of infection (MOI) of 0.05 in the presence of varying concentrations of the test drugs. DMSO was used in the controls. Efficacies were evaluated by quantification of viral copy numbers in the cell supernatant via quantitative real-time RT-PCR (qRT-PCR) and confirmed with visualization of virus nucleoprotein (NP) expression through immunofluorescence microscopy at 48 h post infection (p.i.) (cytopathic effect was not obvious at this time point of infection). Among the seven tested drugs, high concentrations of three nucleoside analogs including ribavirin (half-maximal effective concentration (EC50) = 109.50 μM, half-cytotoxic concentration (CC50) > 400 μM, selectivity index (SI) > 3.65), penciclovir (EC50 = 95.96 μM, CC50 > 400 μM, SI > 4.17) and favipiravir (EC50 = 61.88 μM, CC50 > 400 μM, SI > 6.46) were required to reduce the viral infection (Fig. 1a and Supplementary information, Fig. S1). However, favipiravir has been shown to be 100% effective in protecting mice against Ebola virus challenge, although its EC50 value in Vero E6 cells was as high as 67 μM, 4 suggesting further in vivo studies are recommended to evaluate this antiviral nucleoside. Nafamostat, a potent inhibitor of MERS-CoV, which prevents membrane fusion, was inhibitive against the 2019-nCoV infection (EC50 = 22.50 μM, CC50 > 100 μM, SI > 4.44). Nitazoxanide, a commercial antiprotozoal agent with an antiviral potential against a broad range of viruses including human and animal coronaviruses, inhibited the 2019-nCoV at a low-micromolar concentration (EC50 = 2.12 μM; CC50 > 35.53 μM; SI > 16.76). Further in vivo evaluation of this drug against 2019-nCoV infection is recommended. Notably, two compounds remdesivir (EC50 = 0.77 μM; CC50 > 100 μM; SI > 129.87) and chloroquine (EC50 = 1.13 μM; CC50 > 100 μM, SI > 88.50) potently blocked virus infection at low-micromolar concentration and showed high SI (Fig. 1a, b). Fig. 1 The antiviral activities of the test drugs against 2019-nCoV in vitro. a Vero E6 cells were infected with 2019-nCoV at an MOI of 0.05 in the treatment of different doses of the indicated antivirals for 48 h. The viral yield in the cell supernatant was then quantified by qRT-PCR. Cytotoxicity of these drugs to Vero E6 cells was measured by CCK-8 assays. The left and right Y-axis of the graphs represent mean % inhibition of virus yield and cytotoxicity of the drugs, respectively. The experiments were done in triplicates. b Immunofluorescence microscopy of virus infection upon treatment of remdesivir and chloroquine. Virus infection and drug treatment were performed as mentioned above. At 48 h p.i., the infected cells were fixed, and then probed with rabbit sera against the NP of a bat SARS-related CoV 2 as the primary antibody and Alexa 488-labeled goat anti-rabbit IgG (1:500; Abcam) as the secondary antibody, respectively. The nuclei were stained with Hoechst dye. Bars, 100 μm. c and d Time-of-addition experiment of remdesivir and chloroquine. For “Full-time” treatment, Vero E6 cells were pre-treated with the drugs for 1 h, and virus was then added to allow attachment for 2 h. Afterwards, the virus–drug mixture was removed, and the cells were cultured with drug-containing medium until the end of the experiment. For “Entry” treatment, the drugs were added to the cells for 1 h before viral attachment, and at 2 h p.i., the virus–drug mixture was replaced with fresh culture medium and maintained till the end of the experiment. For “Post-entry” experiment, drugs were added at 2 h p.i., and maintained until the end of the experiment. For all the experimental groups, cells were infected with 2019-nCoV at an MOI of 0.05, and virus yield in the infected cell supernatants was quantified by qRT-PCR c and NP expression in infected cells was analyzed by Western blot d at 14 h p.i. Remdesivir has been recently recognized as a promising antiviral drug against a wide array of RNA viruses (including SARS/MERS-CoV 5 ) infection in cultured cells, mice and nonhuman primate (NHP) models. It is currently under clinical development for the treatment of Ebola virus infection. 6 Remdesivir is an adenosine analogue, which incorporates into nascent viral RNA chains and results in pre-mature termination. 7 Our time-of-addition assay showed remdesivir functioned at a stage post virus entry (Fig. 1c, d), which is in agreement with its putative anti-viral mechanism as a nucleotide analogue. Warren et al. showed that in NHP model, intravenous administration of 10 mg/kg dose of remdesivir resulted in concomitant persistent levels of its active form in the blood (10 μM) and conferred 100% protection against Ebola virus infection. 7 Our data showed that EC90 value of remdesivir against 2019-nCoV in Vero E6 cells was 1.76 μM, suggesting its working concentration is likely to be achieved in NHP. Our preliminary data (Supplementary information, Fig. S2) showed that remdesivir also inhibited virus infection efficiently in a human cell line (human liver cancer Huh-7 cells), which is sensitive to 2019-nCoV. 2 Chloroquine, a widely-used anti-malarial and autoimmune disease drug, has recently been reported as a potential broad-spectrum antiviral drug. 8,9 Chloroquine is known to block virus infection by increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV. 10 Our time-of-addition assay demonstrated that chloroquine functioned at both entry, and at post-entry stages of the 2019-nCoV infection in Vero E6 cells (Fig. 1c, d). Besides its antiviral activity, chloroquine has an immune-modulating activity, which may synergistically enhance its antiviral effect in vivo. Chloroquine is widely distributed in the whole body, including lung, after oral administration. The EC90 value of chloroquine against the 2019-nCoV in Vero E6 cells was 6.90 μM, which can be clinically achievable as demonstrated in the plasma of rheumatoid arthritis patients who received 500 mg administration. 11 Chloroquine is a cheap and a safe drug that has been used for more than 70 years and, therefore, it is potentially clinically applicable against the 2019-nCoV. Our findings reveal that remdesivir and chloroquine are highly effective in the control of 2019-nCoV infection in vitro. Since these compounds have been used in human patients with a safety track record and shown to be effective against various ailments, we suggest that they should be assessed in human patients suffering from the novel coronavirus disease. Supplementary information Supplementary information, Materials and Figures

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Author and article information

Contributors

Chaitra Prabhakara:

ORCID: https://orcid.org/0000-0003-0915-4017

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Rashmi Godbole: Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing

Parijat Sil:

ORCID: https://orcid.org/0000-0002-8391-8110

Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing

Sowmya Jahnavi:

ORCID: https://orcid.org/0000-0002-2923-3938

Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing

Shah-e-Jahan Gulzar:

ORCID: https://orcid.org/0000-0003-0489-9888

Role: ConceptualizationRole: Data curationRole: InvestigationRole: Methodology

Thomas S. van Zanten:

ORCID: https://orcid.org/0000-0002-8810-7149

Role: Data curationRole: Formal analysisRole: SoftwareRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Dhruv Sheth:

ORCID: https://orcid.org/0000-0003-2728-3322

Role: Data curationRole: Formal analysisRole: SoftwareRole: Visualization

Neeraja Subhash:

ORCID: https://orcid.org/0000-0002-0241-1984

Role: Methodology

Anchal Chandra:

ORCID: https://orcid.org/0000-0003-4096-4771

Role: MethodologyRole: Writing – review & editing

Akshatha Shivaraj:

ORCID: https://orcid.org/0000-0001-7185-8803

Role: MethodologyRole: Validation

Patricia Panikulam:

ORCID: https://orcid.org/0000-0003-0647-0030

Role: MethodologyRole: Validation

Ibrahim U:

ORCID: https://orcid.org/0000-0003-1374-8969

Role: MethodologyRole: Validation

Vijay Kumar Nuthakki:

ORCID: https://orcid.org/0000-0002-7454-1948

Role: Methodology

Theja Parassini Puthiyapurayil: Role: Methodology

Riyaz Ahmed: Role: Methodology

Ashaq Hussain Najar: Role: Methodology

Sai Manoz Lingamallu:

ORCID: https://orcid.org/0000-0002-0555-7727

Role: Methodology

Snigdhadev Das:

ORCID: https://orcid.org/0000-0003-0604-6862

Role: MethodologyRole: Validation

Bhagyashri Mahajan: Role: MethodologyRole: Validation

Praveen Vemula: Role: ResourcesRole: Supervision

Sandip B. Bharate:

ORCID: https://orcid.org/0000-0001-6081-5787

Role: ResourcesRole: Supervision

Parvinder Pal Singh: Role: ResourcesRole: Supervision

Ram Vishwakarma:

ORCID: https://orcid.org/0000-0002-0752-6238

Role: ResourcesRole: Supervision

Arjun Guha: Role: ConceptualizationRole: SupervisionRole: Writing – review & editing

Varadharajan Sundaramurthy:

ORCID: https://orcid.org/0000-0003-2562-8518

Role: ConceptualizationRole: Funding acquisitionRole: ResourcesRole: SupervisionRole: Writing – review & editing

Satyajit Mayor:

ORCID: https://orcid.org/0000-0001-9842-6963

Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing

Benhur Lee: Role: Editor

Journal

Journal ID (nlm-ta): PLoS Pathog

Journal ID (iso-abbrev): PLoS Pathog

Journal ID (publisher-id): plos

Title: PLoS Pathogens

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Print): 1553-7366

ISSN (Electronic): 1553-7374

Publication date (Electronic): 12 July 2021

Publication date Collection: July 2021

Volume: 17

Issue: 7

Electronic Location Identifier: e1009706

Affiliations

[1 ] National Centre for Biological Sciences (TIFR), Bengaluru, India

[2 ] University of Trans-Disciplinary Health Sciences and Technology (TDU), Bengaluru, India

[3 ] SASTRA University, Thanjavur, India

[4 ] CSIR—Indian Institute of Integrative Medicine, Jammu, India

[5 ] Institute for Stem Cell Science and Regenerative Medicine (inSTEM), Bengaluru, India

[6 ] Manipal Academy of Higher Education (MAHE), Madhav Nagar, Manipal, Karnataka, India

Icahn School of Medicine at Mount Sinai, UNITED STATES

Author notes

The authors have declared that no competing interests exist.

‡ TSvZ and DS also contributed equally to this work.

* E-mail: varadha@ 123456ncbs.res.in (VS); mayor@ 123456ncbs.res.in (SM)

Author information

Chaitra Prabhakara https://orcid.org/0000-0003-0915-4017

Parijat Sil https://orcid.org/0000-0002-8391-8110

Sowmya Jahnavi https://orcid.org/0000-0002-2923-3938

Shah-e-Jahan Gulzar https://orcid.org/0000-0003-0489-9888

Thomas S. van Zanten https://orcid.org/0000-0002-8810-7149

Dhruv Sheth https://orcid.org/0000-0003-2728-3322

Neeraja Subhash https://orcid.org/0000-0002-0241-1984

Anchal Chandra https://orcid.org/0000-0003-4096-4771

Akshatha Shivaraj https://orcid.org/0000-0001-7185-8803

Patricia Panikulam https://orcid.org/0000-0003-0647-0030

Ibrahim U https://orcid.org/0000-0003-1374-8969

Vijay Kumar Nuthakki https://orcid.org/0000-0002-7454-1948

Sai Manoz Lingamallu https://orcid.org/0000-0002-0555-7727

Snigdhadev Das https://orcid.org/0000-0003-0604-6862

Sandip B. Bharate https://orcid.org/0000-0001-6081-5787

Ram Vishwakarma https://orcid.org/0000-0002-0752-6238

Varadharajan Sundaramurthy https://orcid.org/0000-0003-2562-8518

Satyajit Mayor https://orcid.org/0000-0001-9842-6963

Article

Publisher ID: PPATHOGENS-D-21-01108

DOI: 10.1371/journal.ppat.1009706

PMC ID: 8297935

PubMed ID: 34252168

SO-VID: 45eded83-4924-4845-9a29-9d7522108057

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 26 May 2021

Date accepted : 10 June 2021

Page count

Figures: 8, Tables: 0, Pages: 38

Funding

Funded by: national centre for biological sciences

Award ID: graduate fellowship

Award Recipient :

ORCID: https://orcid.org/0000-0003-0915-4017

Chaitra Prabhakara

Funded by: national centre for biological sciences

Award ID: graduate fellowship

Award Recipient :

ORCID: https://orcid.org/0000-0002-8391-8110

Parijat Sil

Funded by: funder-id http://dx.doi.org/10.13039/501100001501, university grants commission;

Award ID: graduate fellowship

Award Recipient : Rashmi Godbole

Funded by: funder-id http://dx.doi.org/10.13039/501100001501, university grants commission;

Award ID: INSPIRE fellowship

Award Recipient :

ORCID: https://orcid.org/0000-0003-0489-9888

Shah-e-Jahan Gulzar

Funded by: national center for biological sciences

Award ID: postdoctoral fellowship

Award Recipient :

ORCID: https://orcid.org/0000-0002-2923-3938

Sowmya Jahnavi

Funded by: funder-id http://dx.doi.org/10.13039/100004410, European Molecular Biology Organization;

Award ID: ALTF 1519-2013

Award Recipient :

ORCID: https://orcid.org/0000-0002-8810-7149

Thomas S. van Zanten

Funded by: national center for biological sciences

Award ID: Campus fellowship

Award Recipient :

ORCID: https://orcid.org/0000-0002-8810-7149

Thomas S. van Zanten

Funded by: funder-id http://dx.doi.org/10.13039/501100009053, The Wellcome Trust DBT India Alliance;

Award ID: IA/E/15/1/502339

Award Recipient :

ORCID: https://orcid.org/0000-0003-4096-4771

Anchal Chandra

Funded by: funder-id http://dx.doi.org/10.13039/501100001502, department of atomic energy, government of india;

Award ID: RTI 4006

Award Recipient :

ORCID: https://orcid.org/0000-0003-2562-8518

Varadharajan Sundaramurthy

Funded by: department of atomic energy, government of india

Award ID: RTI 4006

Award Recipient :

ORCID: https://orcid.org/0000-0001-9842-6963

Satyajit Mayor

Funded by: national center for biological sciences

Award ID: core fund

Award Recipient :

ORCID: https://orcid.org/0000-0003-2562-8518

Varadharajan Sundaramurthy

Funded by: national center for biological sciences

Award ID: core fund

Award Recipient :

ORCID: https://orcid.org/0000-0001-9842-6963

Satyajit Mayor

Funded by: funder-id http://dx.doi.org/10.13039/501100001409, Department of Science and Technology, Ministry of Science and Technology;

Award ID: JC Bose fellowship

Award Recipient :

ORCID: https://orcid.org/0000-0001-9842-6963

Satyajit Mayor

Funded by: funder-id http://dx.doi.org/10.13039/501100009053, The Wellcome Trust DBT India Alliance;

Award ID: IA/M/15/1/502018

Award Recipient :

ORCID: https://orcid.org/0000-0001-9842-6963

Satyajit Mayor

Funded by: funder-id http://dx.doi.org/10.13039/501100009053, The Wellcome Trust DBT India Alliance;

Award ID: IA/M/15/1/502018

Award Recipient :

ORCID: https://orcid.org/0000-0003-0915-4017

Chaitra Prabhakara

Funded by: funder-id http://dx.doi.org/10.13039/501100009053, The Wellcome Trust DBT India Alliance;

Award ID: IA/M/15/1/502018

Award Recipient :

ORCID: https://orcid.org/0000-0002-2923-3938

Sowmya Jahnavi

Funded by: funder-id http://dx.doi.org/10.13039/501100009053, The Wellcome Trust DBT India Alliance;

Award ID: IA/M/15/1/502018

Award Recipient :

ORCID: https://orcid.org/0000-0002-8391-8110

Parijat Sil

Funded by: funder-id http://dx.doi.org/10.13039/501100009053, the wellcome trust dbt india alliance;

Award ID: IA/M/15/1/502018

Award Recipient :

ORCID: https://orcid.org/0000-0002-8810-7149

Thomas S. van Zanten

We acknowledge NCBS-TIFR graduate fellowship (for CP and PS), UGC graduate fellowship (for RG), INSPIRE fellowship (for SG) and NCBS postdoctoral fellowship (for SJ). TSvZ acknowledges EMBO postdoctoral fellowship (ALTF 1519-2013) and NCBS Campus fellowship; AC thanks India Alliance DBT – Wellcome Trust Early career fellowship (IA/E/15/1/502339); VS and SM acknowledge the support of Department of Atomic Energy, Government of India, under Project Identification No. RTI 4006 and NCBS-TIFR-core funds; SM acknowledges J.C. Bose Fellowship from DST, Government of India, and India Alliance DBT – Wellcome Trust Margdarshi fellowship (IA/M/15/1/502018). CP, PS, TSvZ and SJ received support from Margadarshi fellowship grant (IA/M/15/1/502018). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLOS Publication Stage vor-update-to-uncorrected-proof

Publication Update 2021-07-22

Data Availability All relevant data are within the manuscript and its Supporting Information files.

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ScienceOpen disciplines: Infectious disease & Microbiology

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ScienceOpen disciplines: Infectious disease & Microbiology

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Strategies to target SARS-CoV-2 entry and infection using dual mechanisms of inhibition by acidification inhibitors

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Novel Coronavirus Disease COVID-19

Most cited references 95

A Novel Coronavirus from Patients with Pneumonia in China, 2019

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

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