{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T15:21:12Z","timestamp":1774538472897,"version":"3.50.1"},"reference-count":71,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T00:00:00Z","timestamp":1668988800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The CovNucleovir from the faculty of Medicine of Sorbonne University","award":["CoVNucleovir"],"award-info":[{"award-number":["CoVNucleovir"]}]},{"name":"The CovNucleovir from the faculty of Medicine of Sorbonne University","award":["CoVNucleovir"],"award-info":[{"award-number":["CoVNucleovir"]}]},{"name":"The Sorbonne University Foundation","award":["CoVNucleovir"],"award-info":[{"award-number":["CoVNucleovir"]}]},{"name":"The Sorbonne University Foundation","award":["CoVNucleovir"],"award-info":[{"award-number":["CoVNucleovir"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>This work identifies new ligands of the nucleoprotein N of SARS-CoV-2 by in silico screening, which used a new model of N, built from an Alphafold model refined by molecular dynamic simulations. The ligands were neuropeptides, such as substance P (1-7) and enkephalin, bound at a large site of the C-terminal or associated with the N-terminal \u03b2\u2212sheet. The BA4 and BA5 Omicron variants of N also exhibited a large site as in wt N, and an increased flexibility of the BA5 variant, enabling substance P binding. The binding sites of some ligands deduced from modeling in wt N were assessed by mutation studies in surface plasmon resonance experiments. Dynamic light scattering showed that the ligands impeded RNA binding to N, which likely inhibited replication. We suggest that the physiological role of these neuropeptides in neurotransmission, pain and vasodilation for cholecystokinin and substance P could be altered by binding to N. We speculate that N may link between viral replication and multiple pathways leading to long COVID-19 symptoms. Therefore, N may constitute a \u201cdanger hub\u201d that needs to be inhibited, even at high cost for the host. Antivirals targeted to N may therefore reduce the risk of brain fog and stroke, and improve patients\u2019 health.<\/jats:p>","DOI":"10.3390\/molecules27228094","type":"journal-article","created":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T03:13:41Z","timestamp":1669086821000},"page":"8094","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Neuropeptides, New Ligands of SARS-CoV-2 Nucleoprotein, a Potential Link between Replication, Inflammation and Neurotransmission"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0772-8881","authenticated-orcid":false,"given":"Julien","family":"Henri","sequence":"first","affiliation":[{"name":"Laboratoire de Biologie Computationnelle et Quantitative, Institut de Biologie Paris-Seine, UMR-CNRS 7238, Sorbonne Universit\u00e9, F-75005 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laetitia","family":"Minder","sequence":"additional","affiliation":[{"name":"Institut Europ\u00e9en de Chimie et Biologie (IECB), CNRS, INSERM UAR 3033, US001, Univ. Bordeaux, F-33000 Bordeaux, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Mohanasundaram","sequence":"additional","affiliation":[{"name":"Saint Antoine Hospital, Centre de Recherche Saint Antoine, Sorbonne Universit\u00e9, Biology and Cancer Therapeutics, INSERM U938, F-75231 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S\u00e9bastien","family":"Dilly","sequence":"additional","affiliation":[{"name":"Saint Antoine Hospital, Centre de Recherche Saint Antoine, Sorbonne Universit\u00e9, Biology and Cancer Therapeutics, INSERM U938, F-75231 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Goupil-Lamy","sequence":"additional","affiliation":[{"name":"Biovia, Dassault Syst\u00e8mes, 10 Rue Marcel Dassault, CS40501, CEDEX, F-78946 V\u00e9lizy-Villacoublay, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0509-8399","authenticated-orcid":false,"given":"Carmelo","family":"Di Primo","sequence":"additional","affiliation":[{"name":"CNRS, INSERM, ARNA, UMR 5320, U1212, IECB, Univ. Bordeaux, F-33000 Bordeaux, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2703-9728","authenticated-orcid":false,"given":"Anny","family":"Slama Schwok","sequence":"additional","affiliation":[{"name":"Saint Antoine Hospital, Centre de Recherche Saint Antoine, Sorbonne Universit\u00e9, Biology and Cancer Therapeutics, INSERM U938, F-75231 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1936","DOI":"10.1038\/s41467-021-21953-3","article-title":"The SARS-CoV-2 nucleocapsid protein is dynamic, disordered, and phase separates with RNA","volume":"12","author":"Cubuk","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Dinesh, D.C., Chalupska, D., Silhan, J., Koutna, E., Nencka, R., Veverka, V., and Boura, E. (2020). Structural basis of RNA recognition by the SARS-CoV-2 nucleocapsid phosphoprotein. PLoS Pathog., 16.","DOI":"10.1101\/2020.04.02.022194"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1016\/j.apsb.2020.04.009","article-title":"Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites","volume":"10","author":"Kang","year":"2020","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1002\/pro.3909","article-title":"Architecture and self-assembly of the SARS-CoV-2 nucleocapsid protein","volume":"29","author":"Ye","year":"2020","journal-title":"Protein Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1126\/science.abb7498","article-title":"Structure of the RNA-dependent RNA polymerase from COVID-19 virus","volume":"368","author":"Gao","year":"2020","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5885","DOI":"10.1038\/s41467-020-19619-7","article-title":"SARS-CoV-2 structure and replication characterized by in situ cryo-electron tomography","volume":"11","author":"Klein","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Chen, K., Xiao, F., Hu, D., Ge, W., Tian, M., Wang, W., Pan, P., Wu, K., and Wu, J. (2021). SARS-CoV-2 Nucleocapsid Protein Interacts with RIG-I and Represses RIG-Mediated IFN-\u03b2 Production. Viruses, 13.","DOI":"10.3390\/v13010047"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1007\/s11427-020-1692-1","article-title":"SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells","volume":"63","author":"Mu","year":"2020","journal-title":"Sci. China Life Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1038\/s41467-020-20768-y","article-title":"The SARS-CoV-2 nucleocapsid phosphoprotein forms mutually exclusive condensates with RNA and the membrane-associated M protein","volume":"12","author":"Lu","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"109518","DOI":"10.1016\/j.celrep.2021.109518","article-title":"Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms","volume":"36","author":"Peluso","year":"2021","journal-title":"Cell Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e01396-21","DOI":"10.1128\/JVI.01396-21","article-title":"Direct Activation of Endothelial Cells by SARS-CoV-2 Nucleocapsid Protein Is Blocked by Simvastatin","volume":"95","author":"Qian","year":"2021","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Bai, Z., Cao, Y., Liu, W., and Li, J. (2021). The SARS-CoV-2 Nucleocapsid Protein and Its Role in Viral Structure, Biological Functions, and a Potential Target for Drug or Vaccine Mitigation. Viruses, 13.","DOI":"10.3390\/v13061115"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e00014-21","DOI":"10.1128\/JVI.00014-21","article-title":"Nonsteroidal Anti-inflammatory Drugs Dampen the Cytokine and Antibody Response to SARS-CoV-2 Infection","volume":"95","author":"Chen","year":"2021","journal-title":"J. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1016\/j.biocel.2006.02.003","article-title":"Nucleocapsid protein of SARS-CoV activates the expression of cyclooxygenase-2 by binding directly to regulatory elements for nuclear factor-kappa B and CCAAT\/enhancer binding protein","volume":"38","author":"Yan","year":"2006","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"791753","DOI":"10.3389\/fimmu.2021.791753","article-title":"SARS-CoV-2 N Protein Induces Acute Lung Injury in Mice via NF-\u0138B Activation","volume":"12","author":"Xia","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Perico, N., Cortinovis, M., Suter, F., and Remuzzi, G. (2022). Home as the new frontier for the treatment of COVID-19: The case for anti-inflammatory agents. Lancet Infect. Dis.","DOI":"10.1016\/S1473-3099(22)00433-9"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Terrier, O., Dilly, S., Pizzorno, A., Chalupska, D., Humpolickova, J., Bou\u0159a, E., Berenbaum, F., Quideau, S., Lina, B., and F\u00e8ve, B. (2021). Antiviral Properties of the NSAID Drug Naproxen Targeting the Nucleoprotein of SARS-CoV-2 Coronavirus. Molecules, 26.","DOI":"10.3390\/molecules26092593"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Terrier, O., Dilly, S., Pizzorno, A., Henri, J., Berenbaum, F., Lina, B., F\u00e8ve, B., Adnet, F., Sabbah, M., and Rosa-Calatrava, M. (2020). Broad-spectrum antiviral activity of naproxen: From Influenza A to SARS-CoV-2 Coronavirus. bioRxiv.","DOI":"10.1101\/2020.04.30.069922"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7202","DOI":"10.1021\/acs.jmedchem.8b00557","article-title":"From Naproxen Repurposing to Naproxen Analogues and Their Antiviral Activity against Influenza A Virus","volume":"61","author":"Dilly","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1128\/AAC.02335-12","article-title":"Structure-based discovery of the novel antiviral properties of naproxen against the nucleoprotein of influenza A virus","volume":"57","author":"Lejal","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1038\/s41467-022-29440-z","article-title":"Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates","volume":"13","author":"Rutkai","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3528","DOI":"10.1038\/s41467-022-30836-0","article-title":"Long COVID burden and risk factors in 10 UK longitudinal studies and electronic health records","volume":"13","author":"Thompson","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/s12104-021-10014-x","article-title":"(1)H, (13)C and (15)N Backbone chemical shift assignments of the n-terminal and central intrinsically disordered domains of SARS-CoV-2 nucleoprotein","volume":"15","author":"Guseva","year":"2021","journal-title":"Biomol. NMR Assign."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.ijbiomac.2022.01.094","article-title":"Dimerization of SARS-CoV-2 nucleocapsid protein affects sensitivity of ELISA based diagnostics of COVID-19","volume":"200","author":"Khan","year":"2022","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e105938","DOI":"10.15252\/embj.2020105938","article-title":"Structures of the SARS-CoV-2 nucleocapsid and their perspectives for drug design","volume":"39","author":"Peng","year":"2020","journal-title":"EMBO J."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Di, D., Dileepan, M., Ahmed, S., Liang, Y., and Ly, H. (2021). Recombinant SARS-CoV-2 Nucleocapsid Protein: Expression, Purification, and Its Biochemical Characterization and Utility in Serological Assay Development to Assess Immunological Responses to SARS-CoV-2 Infection. Pathogens, 10.","DOI":"10.3390\/pathogens10081039"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"624765","DOI":"10.3389\/fchem.2020.624765","article-title":"Structural Insight Into the SARS-CoV-2 Nucleocapsid Protein C-Terminal Domain Reveals a Novel Recognition Mechanism for Viral Transcriptional Regulatory Sequences","volume":"8","author":"Yang","year":"2020","journal-title":"Front. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Peronace, C., Tallerico, R., Colosimo, M., Fazio, M., Pasceri, F., Talotta, I., Panduri, G., Pintomalli, L., Oteri, R., and Calantoni, V. (2022). The First Identification in Italy of SARS-CoV-2 Omicron BA.4 Harboring KSF141_del: A Genomic Comparison with Omicron Sub-Variants. Biomedicines, 10.","DOI":"10.20944\/preprints202205.0018.v2"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1016\/j.chom.2021.11.005","article-title":"Nucleocapsid mutations R203K\/G204R increase the infectivity, fitness, and virulence of SARS-CoV-2","volume":"29","author":"Wu","year":"2021","journal-title":"Cell Host Microbe"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/j.bbrc.2020.04.136","article-title":"Biochemical characterization of SARS-CoV-2 nucleocapsid protein","volume":"527","author":"Zeng","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Lechuga, G.C., Souza-Silva, F., Sacramento, C.Q., Trugilho, M.R.O., Valente, R.H., Napoleao-Pego, P., Dias, S.S.G., Fintelman-Rodrigues, N., Temerozo, J.R., and Carels, N. (2021). SARS-CoV-2 Proteins Bind to Hemoglobin and Its Metabolites. Int. J. Mol. Sci., 22.","DOI":"10.1101\/2021.04.16.440124"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e00798","DOI":"10.1002\/prp2.798","article-title":"p-cymene impairs SARS-CoV-2 and Influenza A (H1N1) viral replication: In Silico predicted interaction with SARS-CoV-2 nucleocapsid protein and H1N1 nucleoprotein","volume":"9","author":"Panagiotopoulos","year":"2021","journal-title":"Pharm. Res. Perspect."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1177\/135965350601100803","article-title":"Indomethacin has a potent antiviral activity against SARS coronavirus","volume":"11","author":"Amici","year":"2006","journal-title":"Antivir. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1038\/s41467-021-21903-z","article-title":"SARS-CoV-2 hijacks folate and one-carbon metabolism for viral replication","volume":"12","author":"Zhang","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_36","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."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Ricke-Hoch, M., Stelling, E., Lasswitz, L., Gunesch, A.P., Kasten, M., Zapatero-Belinchon, F.J., Brogden, G., Gerold, G., Pietschmann, T., and Montiel, V. (2021). Impaired immune response mediated by prostaglandin E2 promotes severe COVID-19 disease. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0255335"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"103331","DOI":"10.1016\/j.isci.2021.103331","article-title":"DCcov: Repositioning of drugs and drug combinations for SARS-CoV-2 infected lung through constraint-based modeling","volume":"24","author":"Kishk","year":"2021","journal-title":"iScience"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"10389","DOI":"10.1038\/s41598-022-15107-8","article-title":"Author Correction: An open label randomized clinical trial of Indomethacin for mild and moderate hospitalised COVID-19 patients","volume":"12","author":"Ravichandran","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"293","DOI":"10.2217\/fvl-2020-0398","article-title":"Do fever-relieving medicines have anti-COVID activity: An in silico insight","volume":"16","author":"Shah","year":"2021","journal-title":"Future Virol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"727593","DOI":"10.3389\/fmed.2021.727593","article-title":"Substance P\/Neurokinin-1 Receptor, Trigeminal Ganglion, Latency, and Coronavirus Infection-Is There Any Link?","volume":"8","author":"Mehboob","year":"2021","journal-title":"Front. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e74443","DOI":"10.7554\/eLife.74443","article-title":"Efferocytosis of SARS-CoV-2-infected dying cells impairs macrophage anti-inflammatory functions and clearance of apoptotic cells","volume":"11","author":"Salina","year":"2022","journal-title":"eLife"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e80699","DOI":"10.7554\/eLife.80699","article-title":"COVID-19: Locked in a pro-inflammatory state","volume":"11","author":"Chau","year":"2022","journal-title":"eLife"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/s41589-021-00890-8","article-title":"Selective G protein signaling driven by substance P-neurokinin receptor dynamics","volume":"18","author":"Harris","year":"2022","journal-title":"Nat. Chem. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"117276","DOI":"10.1016\/j.jns.2020.117276","article-title":"Neuropathological explanation of minimal COVID-19 infection rate in newborns, infants and children\u2014A mystery so far. New insight into the role of Substance P","volume":"420","author":"Mehboob","year":"2021","journal-title":"J. Neurol. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1146\/annurev-neuro-080317-061522","article-title":"Endogenous and Exogenous Opioids in Pain","volume":"41","author":"Corder","year":"2018","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"12490","DOI":"10.1523\/JNEUROSCI.2238-14.2014","article-title":"Substance P exacerbates dopaminergic neurodegeneration through neurokinin-1 receptor-independent activation of microglial NADPH oxidase","volume":"34","author":"Wang","year":"2014","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e14796","DOI":"10.14814\/phy2.14796","article-title":"Between two storms, vasoactive peptides or bradykinin underlie severity of COVID-19?","volume":"9","author":"Karamyan","year":"2021","journal-title":"Physiol. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Lattmann, E., Bhalerao, P., ShashiBhushan, B.L., Nargundkar, N., Lattmann, P., Pillai, K.S., and Balaram, P.N. (2021). Randomized, Comparative, Clinical Trial to Evaluate Efficacy and Safety of PNB001 in Moderate COVID-19 Patients. medRxiv.","DOI":"10.1101\/2021.04.16.21255256"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"100098","DOI":"10.1016\/j.sintl.2021.100098","article-title":"Critical neurological features of COVID-19: Role of imaging methods and biosensors for effective diagnosis","volume":"2","author":"Singh","year":"2021","journal-title":"Sens. Int."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1186\/s12974-021-02335-4","article-title":"Chemokine CCL2 prevents opioid-induced inhibition of nociceptive synaptic transmission in spinal cord dorsal horn","volume":"18","author":"Heles","year":"2021","journal-title":"J. Neuroinflammation"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/j.yjmcc.2009.07.025","article-title":"Mechanistic insights into folic acid-dependent vascular protection: Dihydrofolate reductase (DHFR)-mediated reduction in oxidant stress in endothelial cells and angiotensin II-infused mice: A novel HPLC-based fluorescent assay for DHFR activity","volume":"47","author":"Gao","year":"2009","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"118","DOI":"10.2337\/db06-0288","article-title":"Attenuation of angiotensin II signaling recouples eNOS and inhibits nonendothelial NOX activity in diabetic mice","volume":"56","author":"Oak","year":"2007","journal-title":"Diabetes"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1016\/j.vaccine.2004.09.022","article-title":"Immune response to influenza vaccine in healthy adults and the elderly: Association with nutritional status","volume":"23","author":"Hara","year":"2005","journal-title":"Vaccine"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"12559","DOI":"10.1074\/jbc.M111.317040","article-title":"Influence of physiologic folate deficiency on human papillomavirus type 16 (HPV16)-harboring human keratinocytes in vitro and in vivo","volume":"287","author":"Xiao","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Ziganshyna, S., Szczepankiewicz, G., Kuehnert, M., Schulze, A., Liebert, U.G., Pietsch, C., Eulenburg, V., and Werdehausen, R. (2022). Photodynamic Inactivation of SARS-CoV-2 Infectivity and Antiviral Treatment Effects In Vitro. Viruses, 14.","DOI":"10.3390\/v14061301"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"102324","DOI":"10.1016\/j.pdpdt.2021.102324","article-title":"SARS-CoV-2, hemoglobin and protoporphyrin IX: Interactions and perspectives","volume":"34","author":"Courrol","year":"2021","journal-title":"Photodiagnosis Photodyn. Ther."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Chang, C., Michalska, K., Jedrzejczak, R., Maltseva, N., Endres, M., Godzik, A., Kim, Y., and Joachimiak, A. (2020). Crystal structure of RNA binding domain of nucleocapsid phosphoprotein from SARS coronavirus 2. Protein Data Bank.","DOI":"10.2210\/pdb6vyo\/pdb"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/s41592-022-01488-1","article-title":"ColabFold: Making protein folding accessible to all","volume":"19","author":"Mirdita","year":"2022","journal-title":"Nat. Methods"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2856","DOI":"10.1093\/bioinformatics\/bty1057","article-title":"MMseqs2 desktop and local web server app for fast, interactive sequence searches","volume":"35","author":"Mirdita","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"10089","DOI":"10.1063\/1.464397","article-title":"Particle mesh Ewald: An N\u22c5log(N) method for Ewald sums in large systems","volume":"98","author":"Darden","year":"1993","journal-title":"J. Chem. Phys."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1006\/jmbi.1993.1626","article-title":"Comparative protein modeling by satisfaction of spatial restraints","volume":"234","author":"Blundell","year":"1993","journal-title":"J. Mol. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1002\/jcc.540040211","article-title":"CHARMM: A program for macromolec ular energy, minimization, and dynamics calculations","volume":"4","author":"Brooks","year":"1983","journal-title":"J. Comput. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"146366","DOI":"10.1016\/j.brainres.2019.146366","article-title":"Cervical sympathectomy modulates the neurogenic inflammatory neuropeptides following experimental subarachnoid hemorrhage in rats","volume":"1722","author":"Dagistan","year":"2019","journal-title":"Brain Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1186\/s13054-015-0911-z","article-title":"Serum substance P levels are associated with severity and mortality in patients with severe traumatic brain injury","volume":"19","author":"Lorente","year":"2015","journal-title":"Crit. Care"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"29","DOI":"10.29245\/2572.942X\/2016\/2.1020","article-title":"Substance P and Antagonists of the Neurokinin-1 Receptor in Neuroinflammation Associated with Infectious and Neurodegenerative Diseases of the Central Nervous System","volume":"1","author":"Martinez","year":"2016","journal-title":"J. Neurol. Neuromedicine"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1002\/mds.28391","article-title":"Proenkephalin Decreases in Cerebrospinal Fluid with Symptom Progression of Huntington\u2019s Disease","volume":"36","author":"Niemela","year":"2021","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1159\/000330419","article-title":"Plasma substance P levels in patients with persistent cough","volume":"82","author":"Otsuka","year":"2011","journal-title":"Respiration"},{"key":"ref_69","first-page":"OA4114","article-title":"Late Breaking Abstract\u2014Increased Substance P levels in COVID-19 hospitalized patients","volume":"58","author":"Smieszek","year":"2021","journal-title":"Eur. Respir. J."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Tyagi, A., Daliri, E.B.-M., Kwami Ofosu, F., Yeon, S.-J., and Oh, D.-H. (2020). Food-Derived Opioid Peptides in Human Health: A Review. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228825"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Boaventura, P., Macedo, S., Ribeiro, F., Jaconiano, S., and Soares, P. (2022). Post-COVID-19 Condition: Where Are We Now?. Life, 12.","DOI":"10.3390\/life12040517"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/22\/8094\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:22:57Z","timestamp":1760145777000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/22\/8094"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,21]]},"references-count":71,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["molecules27228094"],"URL":"https:\/\/doi.org\/10.3390\/molecules27228094","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,21]]}}}