{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T01:23:22Z","timestamp":1772501002747,"version":"3.50.1"},"reference-count":51,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,25]],"date-time":"2022-12-25T00:00:00Z","timestamp":1671926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI170187"],"award-info":[{"award-number":["R01AI170187"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"APC","award":["R01AI170187"],"award-info":[{"award-number":["R01AI170187"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Evidence suggests that the N-terminal domain (NTD) of the SARS-CoV-2 spike protein interacts with host coreceptors that participate in viral entry. Resolving the identity of coreceptors has important clinical implications as it may provide the basis for the development of antiviral drugs and vaccine candidates. The majority of characteristic mutations in variants of concern (VOCs) have occurred in the NTD and receptor binding domain (RBD). Unlike the RBD, mutations in the NTD have clustered in the most flexible parts of the spike protein. Many possible coreceptors have been proposed, including various sugars such as gangliosides, sialosides, and heparan sulfate. Protein coreceptors, including neuropilin-1 and leucine-rich repeat containing 15 (LRRC15), are also proposed coreceptors that engage the NTD.<\/jats:p>","DOI":"10.3390\/v15010067","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T07:02:12Z","timestamp":1672124532000},"page":"67","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["The Elusive Coreceptors for the SARS-CoV-2 Spike Protein"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2242-5099","authenticated-orcid":false,"given":"Reed L.","family":"Berkowitz","sequence":"first","affiliation":[{"name":"Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4696-875X","authenticated-orcid":false,"given":"David A.","family":"Ostrov","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1146\/annurev-virology-110615-042301","article-title":"Structure, Function, and Evolution of Coronavirus Spike Proteins","volume":"3","author":"Li","year":"2016","journal-title":"Annu. Rev. Virol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1038\/s41401-020-0485-4","article-title":"Structural and functional properties of SARS-CoV-2 spike protein: Potential antivirus drug development for COVID-19","volume":"41","author":"Huang","year":"2020","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/s00284-022-02807-7","article-title":"SARS-CoV-2: Receptor and Co-receptor Tropism Probability","volume":"79","author":"Eslami","year":"2022","journal-title":"Curr. Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Awasthi, M., Gulati, S., Sarkar, D.P., Tiwari, S., Kateriya, S., Ranjan, P., and Verma, S.K. (2020). The Sialoside-Binding Pocket of SARS-CoV-2 Spike Glycoprotein Structurally Resembles MERS-CoV. Viruses, 12.","DOI":"10.3390\/v12090909"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.bbrc.2021.11.059","article-title":"Emerging mutation patterns in SARS-CoV-2 variants","volume":"586","author":"Ostrov","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/s41392-020-00426-x","article-title":"CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells","volume":"5","author":"Wang","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"835994","DOI":"10.3389\/fimmu.2022.835994","article-title":"CCR5 as a Coreceptor for Human Immunodeficiency Virus and Simian Immunodeficiency Viruses: A Prototypic Love-Hate Affair","volume":"13","author":"Jasinska","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3452","DOI":"10.1016\/j.cell.2021.05.032","article-title":"An infectivity-enhancing site on the SARS-CoV-2 spike protein targeted by antibodies","volume":"184","author":"Liu","year":"2021","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s41392-021-00863-2","article-title":"SARS-CoV-2 Omicron RBD shows weaker binding affinity than the currently dominant Delta variant to human ACE2","volume":"7","author":"Wu","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1016\/j.cell.2020.09.018","article-title":"Molecular Architecture of the SARS-CoV-2 Virus","volume":"183","author":"Yao","year":"2020","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"690655","DOI":"10.3389\/fmolb.2021.690655","article-title":"In-Silico Evidence for a Two Receptor Based Strategy of SARS-CoV-2","volume":"8","author":"Milanetti","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Burckhardt, C.J., and Greber, U.F. (2009). Virus Movements on the Plasma Membrane Support Infection and Transmission between Cells. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000621"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"16099","DOI":"10.1038\/s41598-020-73162-5","article-title":"Ultrastructural analysis of SARS-CoV-2 interactions with the host cell via high resolution scanning electron microscopy","volume":"10","author":"Caldas","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5010","DOI":"10.1111\/febs.15651","article-title":"The structural basis of accelerated host cell entry by SARS-CoV-2","volume":"288","author":"Seyran","year":"2021","journal-title":"FEBS J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1016\/j.scib.2021.01.010","article-title":"Binding of the SARS-CoV-2 Spike Protein to Glycans","volume":"66","author":"Hao","year":"2021","journal-title":"Sci. Bull."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2046","DOI":"10.1021\/acscentsci.0c00855","article-title":"The SARS-COV-2 Spike Protein Binds Sialic Acids and Enables Rapid Detection in a Lateral Flow Point of Care Diagnostic Device","volume":"6","author":"Baker","year":"2020","journal-title":"ACS Cent. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e61552","DOI":"10.7554\/eLife.61552","article-title":"Inhibition of SARS-CoV-2 viral entry upon blocking N- and O-glycan elaboration","volume":"9","author":"Yang","year":"2020","journal-title":"eLife"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1038\/s41467-020-20457-w","article-title":"Host and viral determinants for efficient SARS-CoV-2 infection of the human lung","volume":"12","author":"Chu","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1093\/glycob\/cwab032","article-title":"The role of cell surface sialic acids for SARS-CoV-2 infection","volume":"31","author":"Sun","year":"2021","journal-title":"Glycobiology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/s41589-021-00924-1","article-title":"Sialic Acid-Containing Glycolipids Mediate Binding and Viral Entry of SARS-CoV-2","volume":"18","author":"Nguyen","year":"2022","journal-title":"Nat Chem Biol"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"105960","DOI":"10.1016\/j.ijantimicag.2020.105960","article-title":"Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection","volume":"55","author":"Fantini","year":"2020","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_22","first-page":"100268","article-title":"Hydroxychloroquine for COVID19: The curtains close on a comedy of errors","volume":"11","author":"Schwartz","year":"2022","journal-title":"Lancet Reg. Health Am."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"(2019). Cagno; Tseligka; Jones; Tapparel Heparan Sulfate Proteoglycans and Viral Attachment: True Receptors or Adaptation Bias?. Viruses, 11.","DOI":"10.3390\/v11070596"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/j.cell.2020.09.033","article-title":"SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2","volume":"183","author":"Clausen","year":"2020","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"102439","DOI":"10.1016\/j.sbi.2022.102439","article-title":"Spike-heparan sulfate interactions in SARS-CoV-2 infection","volume":"76","author":"Kearns","year":"2022","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1021\/acscentsci.1c00010","article-title":"Heparan Sulfate Proteoglycans as Attachment Factor for SARS-CoV-2","volume":"7","author":"Liu","year":"2021","journal-title":"ACS Cent. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"13221","DOI":"10.1128\/JVI.02078-14","article-title":"Human Coronavirus NL63 Utilizes Heparan Sulfate Proteoglycans for Attachment to Target Cells","volume":"88","author":"Milewska","year":"2014","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Lang, J., Yang, N., Deng, J., Liu, K., Yang, P., Zhang, G., and Jiang, C. (2011). Inhibition of SARS Pseudovirus Cell Entry by Lactoferrin Binding to Heparan Sulfate Proteoglycans. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023710"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1080\/22221751.2021.1888660","article-title":"The in vitro antiviral activity of lactoferrin against common human coronaviruses and SARS-CoV-2 is mediated by targeting the heparan sulfate co-receptor","volume":"10","author":"Hu","year":"2021","journal-title":"Emerg. Microbes Infect."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1016\/j.ijbiomac.2021.10.112","article-title":"SARS-CoV-2 spike protein causes blood coagulation and thrombosis by competitive binding to heparan sulfate","volume":"193","author":"Zheng","year":"2021","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.4161\/auto.7.9.16464","article-title":"Leucine-rich repeat (LRR) proteins: Integrators of pattern recognition and signaling in immunity","volume":"7","author":"Ng","year":"2011","journal-title":"Autophagy"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1158\/0008-5472.CAN-21-3734","article-title":"Exploiting LRRC15 as a Novel Therapeutic Target in Cancer","volume":"82","author":"Ray","year":"2022","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5933","DOI":"10.1128\/JVI.02273-07","article-title":"Tumor Antigen LRRC15 Impedes Adenoviral Infection: Implications for Virus-Based Cancer Therapy","volume":"82","author":"Wilkinson","year":"2008","journal-title":"J. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Shilts, J., Crozier, T.W.M., Teixeira-Silva, A., Gabaev, I., Greenwood, E.J.D., Watson, S.J., Ortmann, B.M., Gawden-Bone, C.M., Pauzaite, T., and Hoffmann, M. (2021). LRRC15 mediates an accessory interaction with the SARS-CoV-2 spike protein. bioRxiv.","DOI":"10.1101\/2021.09.25.461776"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Loo, L., Waller, M.A., Cole, A.J., Stella, A.O., Moreno, C.L., Denes, C.E., Hamoudi, Z., Chung, F., Aggarwal, A., and Low, J.K.K. (2021). LRRC15 suppresses SARS-CoV-2 infection and controls collagen production. bioRxiv.","DOI":"10.21203\/rs.3.rs-1172665\/v1"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1006\/bbrc.2001.6272","article-title":"A Novel Member of the Leucine-Rich Repeat Superfamily Induced in Rat Astrocytes by \u03b2-Amyloid","volume":"290","author":"Satoh","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Song, J., Chow, R.D., Pena-Hernandez, M., Zhang, L., Loeb, S.A., So, E.-Y., Liang, O.D., Wilen, C.B., and Lee, S. (2021). LRRC15 is an inhibitory receptor blocking SARS-CoV-2 spike-mediated entry in trans. bioRxiv.","DOI":"10.1101\/2021.11.23.469714"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Gudowska-Sawczuk, M., and Mroczko, B. (2021). The Role of Neuropilin-1 (NRP-1) in SARS-CoV-2 Infection: Review. J. Clin. Med., 10.","DOI":"10.3390\/jcm10132772"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1126\/science.abd2985","article-title":"Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity","volume":"370","author":"Ojha","year":"2020","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1126\/science.abd3072","article-title":"Neuropilin-1 is a host factor for SARS-CoV-2 infection","volume":"370","author":"Daly","year":"2020","journal-title":"Science"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1038\/s41564-021-00908-w","article-title":"The furin cleavage site in the SARS-CoV-2 spike protein is required for transmission in ferrets","volume":"6","author":"Peacock","year":"2021","journal-title":"Nat. Microbiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2876","DOI":"10.3389\/fimmu.2018.02876","article-title":"Restriction Factors: From Intrinsic Viral Restriction to Shaping Cellular Immunity Against HIV-1","volume":"9","author":"Ruiz","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Winstone, H., Lista, M.J., Reid, A.C., Bouton, C., Pickering, S., Galao, R.P., Kerridge, C., Doores, K.J., Swanson, C.M., and Neil, S.J.D. (2021). The Polybasic Cleavage Site in SARS-CoV-2 Spike Modulates Viral Sensitivity to Type I Interferon and IFITM2. J. Virol., 95.","DOI":"10.1128\/JVI.02422-20"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1038\/s41586-022-04474-x","article-title":"Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity","volume":"603","author":"Meng","year":"2022","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"104270","DOI":"10.1016\/j.ebiom.2022.104270","article-title":"SARS-CoV-2 Omicron BA.5: Evolving tropism and evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern","volume":"84","author":"Aggarwal","year":"2022","journal-title":"eBioMedicine"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.molmed.2008.06.002","article-title":"Sialic acids in human health and disease","volume":"14","author":"Varki","year":"2008","journal-title":"Trends Mol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"537","DOI":"10.5650\/jos.60.537","article-title":"Structures, Biosynthesis, and Functions of Gangliosides-an Overview","volume":"60","author":"Yu","year":"2011","journal-title":"J. Oleo Sci."},{"key":"ref_48","unstructured":"Centers for Disease Control and Prevention (2022). SARS-CoV-2 Variant Classifications and Definitions 2022."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1126\/science.abb2507","article-title":"Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation","volume":"367","author":"Wrapp","year":"2020","journal-title":"Science"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"W365","DOI":"10.1093\/nar\/gkx407","article-title":"HDOCK: A web server for protein\u2013protein and protein\u2013DNA\/RNA docking based on a hybrid strategy","volume":"45","author":"Yan","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"W296","DOI":"10.1093\/nar\/gky427","article-title":"SWISS-MODEL: Homology modelling of protein structures and complexes","volume":"46","author":"Waterhouse","year":"2018","journal-title":"Nucleic Acids Res."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/1\/67\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:50:49Z","timestamp":1760147449000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/1\/67"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,25]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["v15010067"],"URL":"https:\/\/doi.org\/10.3390\/v15010067","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,25]]}}}