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SARS-CoV-2 spike protein dictates syncytium-mediated lymphocyte elimination

Zhang et al., Cell Death & Differentiation, doi:10.1038/s41418-021-00782-3

Apr 2021

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HCQ for COVID-19

1st treatment shown to reduce risk in March 2020

^*, now with p < 0.00000000001 from 417 studies, recognized in 46 countries.

Lower risk for mortality, hospitalization, progression, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine treatments. ^* >10% efficacy, ≥3 studies.

4,900+ studies for 104 treatments. c19hcq.org

In Vitro study showing that SARS-CoV-2 spike protein induces rapid cell fusion and formation of syncytia that internalize and kill lymphocytes, potentially contributing to lymphocytopenia in COVID-19 patients. A bi-arginine motif in the spike protein S1/S2 cleavage site was found to control membrane fusion and syncytia formation. Several candidate antiviral compounds, including arbidol, 6-D-Arg, Con A, NH4Cl, and hydroxychloroquine, inhibited spike protein processing, membrane fusion, syncytia formation, and lymphocyte internalization in 293T-ACE2 cells expressing the SARS-CoV-2 spike protein.

37 preclinical studies support the efficacy of HCQ for COVID-19:

10 In Silico studies1-10

24 In Vitro studies1,11-33

3 In Vivo animal studies15,25,34

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1. González-Paz et al., Biophysical Analysis of Potential Inhibitors of SARS-CoV-2 Cell Recognition and Their Effect on Viral Dynamics in Different Cell Types: A Computational Prediction from In Vitro Experimental Data, ACS Omega, doi:10.1021/acsomega.3c06968.acs.org, doi.org.

2. Alkafaas et al., A study on the effect of natural products against the transmission of B.1.1.529 Omicron, Virology Journal, doi:10.1186/s12985-023-02160-6.biomedcentral.com, doi.org.

3. Nguyen et al., The Potential of Ameliorating COVID-19 and Sequelae From Andrographis paniculata via Bioinformatics, Bioinformatics and Biology Insights, doi:10.1177/11779322221149622.sagepub.com, doi.org.

4. Navya et al., A computational study on hydroxychloroquine binding to target proteins related to SARS-COV-2 infection, Informatics in Medicine Unlocked, doi:10.1016/j.imu.2021.100714.sciencedirect.com, doi.org.

5. Yadav et al., Repurposing the Combination Drug of Favipiravir, Hydroxychloroquine and Oseltamivir as a Potential Inhibitor Against SARS-CoV-2: A Computational Study, Research Square, doi:10.21203/rs.3.rs-628277/v1.researchsquare.com, doi.org.

6. Hussein et al., Molecular Docking Identification for the efficacy of Some Zinc Complexes with Chloroquine and Hydroxychloroquine against Main Protease of COVID-19, Journal of Molecular Structure, doi:10.1016/j.molstruc.2021.129979.sciencedirect.com, doi.org.

7. Baildya et al., Inhibitory capacity of Chloroquine against SARS-COV-2 by effective binding with Angiotensin converting enzyme-2 receptor: An insight from molecular docking and MD-simulation studies, Journal of Molecular Structure, doi:10.1016/j.molstruc.2021.129891.sciencedirect.com, doi.org.

8. Noureddine et al., Quantum chemical studies on molecular structure, AIM, ELF, RDG and antiviral activities of hybrid hydroxychloroquine in the treatment of COVID-19: molecular docking and DFT calculations, Journal of King Saud University - Science, doi:10.1016/j.jksus.2020.101334.sciencedirect.com, doi.org.

9. Tarek et al., Pharmacokinetic Basis of the Hydroxychloroquine Response in COVID-19: Implications for Therapy and Prevention, European Journal of Drug Metabolism and Pharmacokinetics, doi:10.1007/s13318-020-00640-6.springer.com, doi.org.

10. Rowland Yeo et al., Impact of Disease on Plasma and Lung Exposure of Chloroquine, Hydroxychloroquine and Azithromycin: Application of PBPK Modeling, Clinical Pharmacology & Therapeutics, doi:10.1002/cpt.1955.wiley.com, doi.org.

11. Hitti et al., Hydroxychloroquine attenuates double-stranded RNA-stimulated hyper-phosphorylation of tristetraprolin/ZFP36 and AU-rich mRNA stabilization, Immunology, doi:10.1111/imm.13835.wiley.com, doi.org.

12. Yan et al., Super-resolution imaging reveals the mechanism of endosomal acidification inhibitors against SARS-CoV-2 infection, ChemBioChem, doi:10.1002/cbic.202400404.wiley.com, doi.org.

13. Mohd Abd Razak et al., In Vitro Anti-SARS-CoV-2 Activities of Curcumin and Selected Phenolic Compounds, Natural Product Communications, doi:10.1177/1934578X231188861.sagepub.com, doi.org.

14. Alsmadi et al., The In Vitro, In Vivo, and PBPK Evaluation of a Novel Lung-Targeted Cardiac-Safe Hydroxychloroquine Inhalation Aerogel, AAPS PharmSciTech, doi:10.1208/s12249-023-02627-3.springer.com, doi.org.

15. Wen et al., Cholinergic α7 nAChR signaling suppresses SARS-CoV-2 infection and inflammation in lung epithelial cells, Journal of Molecular Cell Biology, doi:10.1093/jmcb/mjad048.oup.com, doi.org.

16. Kamga Kapchoup et al., In vitro effect of hydroxychloroquine on pluripotent stem cells and their cardiomyocytes derivatives, Frontiers in Pharmacology, doi:10.3389/fphar.2023.1128382.frontiersin.org, doi.org.

17. Milan Bonotto et al., Cathepsin inhibitors nitroxoline and its derivatives inhibit SARS-CoV-2 infection, Antiviral Research, doi:10.1016/j.antiviral.2023.105655.sciencedirect.com, doi.org.

18. Miao et al., SIM imaging resolves endocytosis of SARS-CoV-2 spike RBD in living cells, Cell Chemical Biology, doi:10.1016/j.chembiol.2023.02.001.sciencedirect.com, doi.org.

19. Yuan et al., Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture, Communications Biology, doi:10.1038/s42003-022-03841-8.nature.com, doi.org.

20. Faísca et al., Enhanced In Vitro Antiviral Activity of Hydroxychloroquine Ionic Liquids against SARS-CoV-2, Pharmaceutics, doi:10.3390/pharmaceutics14040877.mdpi.com, doi.org.

21. Delandre et al., Antiviral Activity of Repurposing Ivermectin against a Panel of 30 Clinical SARS-CoV-2 Strains Belonging to 14 Variants, Pharmaceuticals, doi:10.3390/ph15040445.mdpi.com, doi.org.

22. Purwati et al., An in vitro study of dual drug combinations of anti-viral agents, antibiotics, and/or hydroxychloroquine against the SARS-CoV-2 virus isolated from hospitalized patients in Surabaya, Indonesia, PLOS One, doi:10.1371/journal.pone.0252302.plos.org, doi.org.

23. Zhang et al., SARS-CoV-2 spike protein dictates syncytium-mediated lymphocyte elimination, Cell Death & Differentiation, doi:10.1038/s41418-021-00782-3.nature.com, doi.org.

24. Dang et al., Structural basis of anti-SARS-CoV-2 activity of hydroxychloroquine: specific binding to NTD/CTD and disruption of LLPS of N protein, bioRxiv, doi:10.1101/2021.03.16.435741.biorxiv.org, doi.org.

25. Shang et al., Inhibitors of endosomal acidification suppress SARS-CoV-2 replication and relieve viral pneumonia in hACE2 transgenic mice, Virology Journal, doi:10.1186/s12985-021-01515-1.biomedcentral.com, doi.org.

26. Wang et al., Chloroquine and hydroxychloroquine as ACE2 blockers to inhibit viropexis of 2019-nCoV Spike pseudotyped virus, Phytomedicine, doi:10.1016/j.phymed.2020.153333.nih.gov, doi.org.

27. Sheaff, R., A New Model of SARS-CoV-2 Infection Based on (Hydroxy)Chloroquine Activity, bioRxiv, doi:10.1101/2020.08.02.232892.biorxiv.org, doi.org.

28. Ou et al., Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2, PLOS Pathogens, doi:10.1371/journal.ppat.1009212.plos.org, doi.org.

29. Andreani et al., In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect, Microbial Pathogenesis, doi:10.1016/j.micpath.2020.104228.sciencedirect.com, doi.org.

30. Clementi et al., Combined Prophylactic and Therapeutic Use Maximizes Hydroxychloroquine Anti-SARS-CoV-2 Effects in vitro, Front. Microbiol., 10 July 2020, doi:10.3389/fmicb.2020.01704.frontiersin.org, doi.org.

31. Liu et al., Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discovery 6, 16 (2020), doi:10.1038/s41421-020-0156-0.nature.com, doi.org.

32. Yao et al., In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Clin. Infect. Dis., 2020 Mar 9, doi:10.1093/cid/ciaa237.oup.com, doi.org.

33. Wang (B) et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res. 30, 269–271, doi:10.1038/s41422-020-0282-0.nature.com, doi.org.

34. Shu-Han Lin et al., Inhalable Chitosan-Based Hydrogel as a Mucosal Adjuvant for Hydroxychloroquine in the Treatment for SARS-CoV-2 Infection in a Hamster Model, Journal of Microbiology, Immunology and Infection, doi:10.1016/j.jmii.2023.08.001.sciencedirect.com, doi.org.

Zhang et al., 20 Apr 2021, peer-reviewed, 27 authors. Contact: liuliang@mails.tjmu.edu.cn, hhongy1999@126.com, sunq@bmi.ac.cn.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

This Paper HCQ All

SARS-CoV-2 spike protein dictates syncytium-mediated lymphocyte elimination

Zhengrong Zhang, You Zheng, Zubiao Niu, Bo Zhang, Chenxi Wang, Xiaohong Yao, Haoran Peng, Del Nonno Franca, Yunyun Wang, Yichao Zhu, Yan Su, Meng Tang, Xiaoyi Jiang, He Ren, Meifang He, Yuqi Wang, Lihua Gao, Ping Zhao, Hanping Shi, Zhaolie Chen, Xiaoning Wang, Mauro Piacentini, Xiuwu Bian, Gerry Melino, Liang Liu, Hongyan Huang, Qiang Sun

Cell Death & Differentiation, doi:10.1038/s41418-021-00782-3

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is highly contagious and causes lymphocytopenia, but the underlying mechanisms are poorly understood. We demonstrate here that heterotypic cell-in-cell structures with lymphocytes inside multinucleate syncytia are prevalent in the lung tissues of coronavirus disease 2019 (COVID-19) patients. These unique cellular structures are a direct result of SARS-CoV-2 infection, as the expression of the SARS-CoV-2 spike glycoprotein is sufficient to induce a rapid (~45.1 nm/s) membrane fusion to produce syncytium, which could readily internalize multiple lines of lymphocytes to form typical cell-in-cell structures, remarkably leading to the death of internalized cells. This membrane fusion is dictated by a bi-arginine motif within the polybasic S1/S2 cleavage site, which is frequently present in the surface glycoprotein of most highly contagious viruses. Moreover, candidate anti-viral drugs could efficiently inhibit spike glycoprotein processing, membrane fusion, and cell-in-cell formation. Together, we delineate a molecular and cellular rationale for SARS-CoV-2 pathogenesis and identify novel targets for COVID-19 therapy.

Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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High frequency of ' 'cell-in-cell formation in heterogeneous human breast cancer tissue in a ' 'patient with poor prognosis: a case report and literature review. Front ' 'Oncol. 2019;9:1444.', 'journal-title': 'Front Oncol'}, { 'key': '782_CR22', 'doi-asserted-by': 'publisher', 'first-page': '20278', 'DOI': '10.18632/oncotarget.4275', 'volume': '6', 'author': 'H Huang', 'year': '2015', 'unstructured': 'Huang H, Chen A, Wang T, Wang M, Ning X, He M, et al. Detecting ' 'cell-in-cell structures in human tumor samples by E-cadherin/CD68/CD45 ' 'triple staining. Oncotarget. 2015;6:20278–87.', 'journal-title': 'Oncotarget'}, { 'key': '782_CR23', 'doi-asserted-by': 'publisher', 'first-page': '119', 'DOI': '10.1038/s41419-021-03396-2', 'volume': '12', 'author': 'Y Su', 'year': '2021', 'unstructured': 'Su Y, Ren H, Tang M, Zheng Y, Zhang B, Wang C, et al. Role and dynamics ' 'of vacuolar pH during cell-in-cell mediated death. Cell Death Dis. ' '2021;12:119.', 'journal-title': 'Cell Death Dis'}, { 'key': '782_CR24', 'doi-asserted-by': 'publisher', 'first-page': '758', 'DOI': '10.1038/s41568-018-0073-9', 'volume': '18', 'author': 'S Fais', 'year': '2018', 'unstructured': 'Fais S, Overholtzer M. Cell-in-cell phenomena in cancer. Nat Rev Cancer. ' '2018;18:758–66.', 'journal-title': 'Nat Rev Cancer'}, { 'key': '782_CR25', 'doi-asserted-by': 'publisher', 'first-page': 'e856', 'DOI': '10.1038/cddis.2013.352', 'volume': '4', 'author': 'S Wang', 'year': '2013', 'unstructured': 'Wang S, He MF, Chen YH, Wang MY, Yu XM, Bai J, et al. Rapid reuptake of ' 'granzyme B leads to emperitosis: an apoptotic cell-in-cell death of ' 'immune killer cells inside tumor cells. Cell Death Dis. 2013;4:e856.', 'journal-title': 'Cell Death Dis'}, { 'key': '782_CR26', 'unstructured': 'Luo W, Yu H, Gou J, Li X, Sun Y, Li J, et al. Clinical pathology of ' 'critical patient with novel coronavirus pneumonia (COVID-19). 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Int J Antimicrob ' 'Agents. 2020;55:105960.', 'journal-title': 'Int J Antimicrob Agents'}, { 'key': '782_CR36', 'doi-asserted-by': 'publisher', 'unstructured': 'Amin M, Abbas G. Docking study of Chloroquine and Hydroxychloroquine ' 'interaction with SARS-CoV-2 spike glycoprotein-An in silico insight into ' 'the comparative efficacy of repurposing antiviral drugs. J Biomol Struct ' 'Dyn. 2020; https://doi.org/10.1080/07391102.2020.1775703:1-11.', 'DOI': '10.1080/07391102.2020.1775703:1-11'}, { 'key': '782_CR37', 'doi-asserted-by': 'publisher', 'unstructured': 'Braga L, Ali H, Secco I, Chiavacci E, Neves G, Goldhill D, et al. Drugs ' 'that inhibit TMEM16 proteins block SARS-CoV-2 Spike-induced syncytia. ' 'Nature. 2021; https://doi.org/10.1038/s41586-021-03491-6.', 'DOI': '10.1038/s41586-021-03491-6'}, { 'key': '782_CR38', 'doi-asserted-by': 'publisher', 'first-page': '1', 'DOI': '10.3389/fcell.2020.00001', 'volume': '8', 'author': 'C Wang', 'year': '2020', 'unstructured': 'Wang C, Chen A, Ruan B, Niu Z, Su Y, Qin H, et al. PCDH7 inhibits the ' 'formation of homotypic cell-in-cell structure. Front Cell Dev Biol. ' '2020;8:1–12.', 'journal-title': 'Front Cell Dev Biol'}], 'container-title': 'Cell Death & Differentiation', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://www.nature.com/articles/s41418-021-00782-3.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://www.nature.com/articles/s41418-021-00782-3', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://www.nature.com/articles/s41418-021-00782-3.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2021, 9, 1]], 'date-time': '2021-09-01T00:26:35Z', 'timestamp': 1630455995000}, 'score': 1, 'resource': {'primary': {'URL': 'https://www.nature.com/articles/s41418-021-00782-3'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2021, 4, 20]]}, 'references-count': 38, 'journal-issue': {'issue': '9', 'published-print': {'date-parts': [[2021, 9]]}}, 'alternative-id': ['782'], 'URL': 'http://dx.doi.org/10.1038/s41418-021-00782-3', 'relation': { 'has-preprint': [ { 'id-type': 'doi', 'id': '10.21203/rs.3.rs-353991/v1', 'asserted-by': 'object'}]}, 'ISSN': ['1350-9047', '1476-5403'], 'subject': [], 'container-title-short': 'Cell Death Differ', 'published': {'date-parts': [[2021, 4, 20]]}, 'assertion': [ { 'value': '22 March 2021', 'order': 1, 'name': 'received', 'label': 'Received', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '7 April 2021', 'order': 2, 'name': 'revised', 'label': 'Revised', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '8 April 2021', 'order': 3, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '20 April 2021', 'order': 4, 'name': 'first_online', 'label': 'First Online', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Compliance with ethical standards'}}, { 'value': 'The authors declare no competing interests.', 'order': 2, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Conflict of interest'}}, { 'value': 'The autopsy for COVID-19 death was carried out with informed consent under the ' 'approval of Ethics Committee of Wuhan Infectious Diseases Hospital ' '(KY-2020-15.01) and Ethics Committee of the First Affiliated Hospital of Army ' 'Medical University (KY2020298).', 'order': 3, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Ethics statement'}}, { 'value': 'This content has been made available to all.', 'name': 'free', 'label': 'Free to read'}]}

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