{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T22:43:25Z","timestamp":1791240205749,"version":"4.1.0"},"reference-count":64,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T00:00:00Z","timestamp":1681948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"USC Mann School of Pharmacy and Pharmaceutical Sciences"},{"name":"John Stauffer Decanal Chair in Pharmaceutical Sciences (USC)"},{"name":"W.M. Keck Foundation COVID-19 Research Fund to the Keck School of Medicine of USC"},{"name":"Johns Hopkins University School of Medicine for COVID research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a SARS-like coronavirus, continues to produce mounting infections and fatalities all over the world. Recent data point to SARS-CoV-2 viral infections in the human testis. As low testosterone levels are associated with SARS-CoV-2 viral infections in males and human Leydig cells are the main source of testosterone, we hypothesized that SARS-CoV-2 could infect human Leydig cells and impair their function. We successfully detected SARS-CoV-2 nucleocapsid in testicular Leydig cells of SARS-CoV-2-infected hamsters, providing evidence that Leydig cells can be infected with SARS-CoV-2. We then employed human Leydig-like cells (hLLCs) to show that the SARS-CoV-2 receptor angiotensin-converting enzyme 2 is highly expressed in hLLCs. Using a cell binding assay and a SARS-CoV-2 spike-pseudotyped viral vector (SARS-CoV-2 spike pseudovector), we showed that SARS-CoV-2 could enter hLLCs and increase testosterone production by hLLCs. We further combined the SARS-CoV-2 spike pseudovector system with pseudovector-based inhibition assays to show that SARS-CoV-2 enters hLLCs through pathways distinct from those of monkey kidney Vero E6 cells, a typical model used to study SARS-CoV-2 entry mechanisms. We finally revealed that neuropilin-1 and cathepsin B\/L are expressed in hLLCs and human testes, raising the possibility that SARS-CoV-2 may enter hLLCs through these receptors or proteases. In conclusion, our study shows that SARS-CoV-2 can enter hLLCs through a distinct pathway and alter testosterone production.<\/jats:p>","DOI":"10.3390\/cells12081198","type":"journal-article","created":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T01:33:43Z","timestamp":1682040823000},"page":"1198","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["SARS-CoV-2 Enters Human Leydig Cells and Affects Testosterone Production In Vitro"],"prefix":"10.3390","volume":"12","author":[{"given":"Lu","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3363-420X","authenticated-orcid":false,"given":"Chantal M.","family":"Sottas","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsu-Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyi","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason S.","family":"Villano","sequence":"additional","affiliation":[{"name":"Departments of Molecular and Comparative Pathobiology, Pathology and Neurology, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph L.","family":"Mankowski","sequence":"additional","affiliation":[{"name":"Departments of Molecular and Comparative Pathobiology, Pathology and Neurology, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula M.","family":"Cannon","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1183-8568","authenticated-orcid":false,"given":"Vassilios","family":"Papadopoulos","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Gralinski, L.E., and Menachery, V.D. (2020). Return of the Coronavirus: 2019-nCoV. Viruses, 12.","DOI":"10.3390\/v12020135"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e9610","DOI":"10.15252\/msb.20209610","article-title":"The protein expression profile of ACE2 in human tissues","volume":"16","author":"Hikmet","year":"2020","journal-title":"Mol. Syst. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/andr.13073","article-title":"Testicular pathology in fatal COVID-19: A descriptive autopsy study","volume":"10","author":"Teixeira","year":"2022","journal-title":"Andrology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"65","DOI":"10.5534\/wjmh.200170","article-title":"Histopathology and Ultrastructural Findings of Fatal COVID-19 Infections on Testis","volume":"39","author":"Achua","year":"2021","journal-title":"World J. Mens Health"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Wang, Z., and Xu, X. (2020). scRNA-seq Profiling of Human Testes Reveals the Presence of the ACE2 Receptor, A Target for SARS-CoV-2 Infection in Spermatogonia, Leydig and Sertoli Cells. Cells, 9.","DOI":"10.20944\/preprints202002.0299.v1"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1111\/andr.12993","article-title":"Severely low testosterone in males with COVID-19: A case-control study","volume":"9","author":"Salonia","year":"2021","journal-title":"Andrology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1111\/andr.13152","article-title":"The association of free testosterone levels with coronavirus disease 2019","volume":"10","author":"Apaydin","year":"2022","journal-title":"Andrology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1111\/andr.13097","article-title":"Testosterone in males with COVID-19: A 7-month cohort study","volume":"10","author":"Salonia","year":"2022","journal-title":"Andrology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/andr.13081","article-title":"The relationship of serum testosterone levels with the clinical course and prognosis of COVID-19 disease in male patients: A prospective study","volume":"10","author":"Cinislioglu","year":"2022","journal-title":"Andrology"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Campos, R.K., Camargos, V.N., Azar, S.R., Haines, C.A., Eyzaguirre, E.J., and Rossi, S.L. (2021). SARS-CoV-2 Infects Hamster Testes. Microorganisms, 9.","DOI":"10.3390\/microorganisms9061318"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e974","DOI":"10.1093\/cid\/ciac142","article-title":"Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection by Intranasal or Intratesticular Route Induces Testicular Damage","volume":"75","author":"Li","year":"2022","journal-title":"Clin. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"23274","DOI":"10.1073\/pnas.1908207116","article-title":"Directing differentiation of human induced pluripotent stem cells toward androgen-producing Leydig cells rather than adrenal cells","volume":"116","author":"Li","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","first-page":"119","article-title":"A robust method to derive functional neural crest cells from human pluripotent stem cells","volume":"2","author":"Kreitzer","year":"2013","journal-title":"Am. J. Stem Cells"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e0096621","DOI":"10.1128\/JVI.00966-21","article-title":"Cytoplasmic Tail Truncation of SARS-CoV-2 Spike Protein Enhances Titer of Pseudotyped Vectors but Masks the Effect of the D614G Mutation","volume":"95","author":"Chen","year":"2021","journal-title":"J. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.jviromet.2010.08.006","article-title":"Generation of VSV pseudotypes using recombinant DeltaG-VSV for studies on virus entry, identification of entry inhibitors, and immune responses to vaccines","volume":"169","author":"Whitt","year":"2010","journal-title":"J. Virol. Methods"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1186\/1479-5876-9-137","article-title":"Generation of high-titer viral preparations by concentration using successive rounds of ultracentrifugation","volume":"9","author":"Ichim","year":"2011","journal-title":"J. Transl. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.ajpath.2021.10.009","article-title":"Progression and Resolution of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Golden Syrian Hamsters","volume":"192","author":"Mulka","year":"2022","journal-title":"Am. J. Pathol."},{"key":"ref_18","unstructured":"Council, N.R. (2010). Guide for the Care and Use of Laboratory Animals, The National Academies Press."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.mce.2011.07.029","article-title":"Prolactin (PRL) induction of cyclooxygenase 2 (COX2) expression and prostaglandin (PG) production in hamster Leydig cells","volume":"348","author":"Matzkin","year":"2012","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1093\/biolre\/iox177","article-title":"The use of purified rat Leydig cells complements the H295R screen to detect chemical-induced alterations in testosterone production","volume":"98","author":"Suarez","year":"2018","journal-title":"Biol. Reprod."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"eabc3582","DOI":"10.1126\/sciimmunol.abc3582","article-title":"TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes","volume":"5","author":"Zang","year":"2020","journal-title":"Sci. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41580-021-00418-x","article-title":"Mechanisms of SARS-CoV-2 entry into cells","volume":"23","author":"Jackson","year":"2022","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e571","DOI":"10.1016\/S2666-5247(21)00216-0","article-title":"Estimating clinical SARS-CoV-2 infectiousness in Vero E6 and primary airway epithelial cells","volume":"2","author":"Hulo","year":"2021","journal-title":"Lancet Microbe"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"107697","DOI":"10.1016\/j.jmgm.2020.107697","article-title":"Prioritizing potential ACE2 inhibitors in the COVID-19 pandemic: Insights from a molecular mechanics-assisted structure-based virtual screening experiment","volume":"100","author":"Terali","year":"2020","journal-title":"J. Mol. Graph. Model."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"103255","DOI":"10.1016\/j.ebiom.2021.103255","article-title":"Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity","volume":"65","author":"Hoffmann","year":"2021","journal-title":"EBioMedicine"},{"key":"ref_28","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_29","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_30","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.3389\/fphar.2020.01161","article-title":"DPP4 and ACE2 in Diabetes and COVID-19: Therapeutic Targets for Cardiovascular Complications?","volume":"11","author":"Valencia","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1016\/j.omtn.2021.10.016","article-title":"Dual inhibition of TMPRSS2 and Cathepsin Bprevents SARS-CoV-2 infection in iPS cells","volume":"26","author":"Hashimoto","year":"2021","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1038\/s41392-021-00558-8","article-title":"Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development","volume":"6","author":"Zhao","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_33","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_34","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.compbiolchem.2008.07.014","article-title":"Discrepancy between mRNA and protein abundance: Insight from information retrieval process in computers","volume":"32","author":"Wang","year":"2008","journal-title":"Comput. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.jsxm.2020.09.013","article-title":"COVID-19 Infection in Men on Testosterone Replacement Therapy","volume":"18","author":"Rambhatla","year":"2021","journal-title":"J. Sex. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/s41585-021-00480-2","article-title":"Advances in stem cell research for the treatment of primary hypogonadism","volume":"18","author":"Li","year":"2021","journal-title":"Nat. Rev. Urol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"694083","DOI":"10.3389\/fendo.2021.694083","article-title":"Testosterone Deficiency Is a Risk Factor for Severe COVID-19","volume":"12","author":"Lanser","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"11727","DOI":"10.1073\/pnas.2003138117","article-title":"Cell entry mechanisms of SARS-CoV-2","volume":"117","author":"Shang","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/s41443-021-00524-6","article-title":"Androgens and COVID-19: Exploring the role of testosterone replacement therapy","volume":"34","author":"Punjani","year":"2022","journal-title":"Int. J. Impot. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s12958-018-0341-2","article-title":"The in vitro modulation of steroidogenesis by inflammatory cytokines and insulin in TM3 Leydig cells","volume":"16","author":"Leisegang","year":"2018","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/andr.12868","article-title":"Why does COVID-19 kill more elderly men than women? Is there a role for testosterone?","volume":"9","author":"Papadopoulos","year":"2021","journal-title":"Andrology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1007\/s41061-021-00353-7","article-title":"The Repurposed ACE2 Inhibitors: SARS-CoV-2 Entry Blockers of Covid-19","volume":"379","author":"Ahmad","year":"2021","journal-title":"Top. Curr. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/s41423-020-00604-5","article-title":"Pathological and molecular examinations of postmortem testis biopsies reveal SARS-CoV-2 infection in the testis and spermatogenesis damage in COVID-19 patients","volume":"18","author":"Ma","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"592737","DOI":"10.3389\/fphar.2020.592737","article-title":"Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2","volume":"11","author":"Chen","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Murgolo, N., Therien, A.G., Howell, B., Klein, D., Koeplinger, K., Lieberman, L.A., Adam, G.C., Flynn, J., McKenna, P., and Swaminathan, G. (2021). SARS-CoV-2 tropism, entry, replication, and propagation: Considerations for drug discovery and development. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009225"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1210\/en.2016-1758","article-title":"The Human Adrenal Gland Proteome Defined by Transcriptomics and Antibody-Based Profiling","volume":"158","author":"Bergman","year":"2017","journal-title":"Endocrinology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6317","DOI":"10.1038\/s41467-020-19741-6","article-title":"Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission","volume":"11","author":"Peckham","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e131","DOI":"10.15190\/d.2021.10","article-title":"SARS-CoV-2 effect on male infertility and its possible pathophysiological mechanisms","volume":"9","author":"Agolli","year":"2021","journal-title":"Discoveries"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e2223","DOI":"10.1002\/rmv.2223","article-title":"Sex-based differences in severity and mortality in COVID-19","volume":"31","author":"Alwani","year":"2021","journal-title":"Rev. Med. Virol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1002\/cpt.2508","article-title":"EXOGENOUS Sex Hormones and Sex Hormone Receptor Modulators in COVID-19: Rationale and Clinical Pharmacology Considerations","volume":"111","author":"Zou","year":"2022","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2016","DOI":"10.1038\/s41467-021-22362-2","article-title":"Lead compounds for the development of SARS-CoV-2 3CL protease inhibitors","volume":"12","author":"Iketani","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"13190","DOI":"10.1073\/pnas.1835675100","article-title":"The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor","volume":"100","author":"Yang","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"6676","DOI":"10.1128\/JVI.75.14.6676-6681.2001","article-title":"Viral replicase gene products suffice for coronavirus discontinuous transcription","volume":"75","author":"Thiel","year":"2001","journal-title":"J. Virol."},{"key":"ref_54","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_55","doi-asserted-by":"crossref","unstructured":"Perez-Miller, S., Patek, M., Moutal, A., Cabel, C.R., Thorne, C.A., Campos, S.K., and Khanna, R. (2020). In silico identification and validation of inhibitors of the interaction between neuropilin receptor 1 and SARS-CoV-2 Spike protein. bioRxiv.","DOI":"10.1101\/2020.09.22.308783"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1097\/j.pain.0000000000002097","article-title":"SARS-CoV-2 spike protein co-opts VEGF-A\/neuropilin-1 receptor signaling to induce analgesia","volume":"162","author":"Moutal","year":"2021","journal-title":"Pain"},{"key":"ref_57","unstructured":"Padmanabhan, P., and Dixit, N.M. (2022). Evidence of increased Cathepsin B\/L and decreased TMPRSS2 usage for cell entry by the SARS-CoV-2 Omicron variant. bioRxiv."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"178","DOI":"10.3389\/fneur.2015.00178","article-title":"Cathepsin B is a New Drug Target for Traumatic Brain Injury Therapeutics: Evidence for E64d as a Promising Lead Drug Candidate","volume":"6","author":"Hook","year":"2015","journal-title":"Front. Neurol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"11876","DOI":"10.1073\/pnas.0505577102","article-title":"Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry","volume":"102","author":"Simmons","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1038\/s41467-020-15562-9","article-title":"Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV","volume":"11","author":"Ou","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"fuaa057","DOI":"10.1093\/femsre\/fuaa057","article-title":"Molecular diversity of coronavirus host cell entry receptors","volume":"45","author":"Millet","year":"2021","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1038\/s41591-021-01283-z","article-title":"Post-acute COVID-19 syndrome","volume":"27","author":"Nalbandian","year":"2021","journal-title":"Nat. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/s41591-021-01292-y","article-title":"Attributes and predictors of long COVID","volume":"27","author":"Sudre","year":"2021","journal-title":"Nat. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"eabq3059","DOI":"10.1126\/scitranslmed.abq3059","article-title":"SARS-CoV-2 infection in hamsters and humans results in lasting and unique systemic perturbations post recovery","volume":"14","author":"Frere","year":"2022","journal-title":"Sci. Transl. Med."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/8\/1198\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:19:45Z","timestamp":1760123985000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/8\/1198"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,20]]},"references-count":64,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["cells12081198"],"URL":"https:\/\/doi.org\/10.3390\/cells12081198","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,20]]}}}