{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T20:32:01Z","timestamp":1782505921240,"version":"3.54.5"},"reference-count":72,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,21]],"date-time":"2021-08-21T00:00:00Z","timestamp":1629504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FIOCRUZ\/INOVA","award":["VPPCB-007FIO-18-2-21, VPPCB-005-FIO-20, and VPPIS-005FIO-20-2-51; B3-Bovespa"],"award-info":[{"award-number":["VPPCB-007FIO-18-2-21, VPPCB-005-FIO-20, and VPPIS-005FIO-20-2-51; B3-Bovespa"]}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["#467.488.2014-2, #301744\/2019-0,"],"award-info":[{"award-number":["#467.488.2014-2, #301744\/2019-0,"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro\/FAPERJ","award":["#110.198-13, #210.003\/2018"],"award-info":[{"award-number":["#110.198-13, #210.003\/2018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>(1) Background: coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been linked to hematological dysfunctions, but there are little experimental data that explain this. Spike (S) and Nucleoprotein (N) proteins have been putatively associated with these dysfunctions. In this work, we analyzed the recruitment of hemoglobin (Hb) and other metabolites (hemin and protoporphyrin IX-PpIX) by SARS-Cov2 proteins using different approaches. (2) Methods: shotgun proteomics (LC\u2013MS\/MS) after affinity column adsorption identified hemin-binding SARS-CoV-2 proteins. The parallel synthesis of the peptides technique was used to study the interaction of the receptor bind domain (RBD) and N-terminal domain (NTD) of the S protein with Hb and in silico analysis to identify the binding motifs of the N protein. The plaque assay was used to investigate the inhibitory effect of Hb and the metabolites hemin and PpIX on virus adsorption and replication in Vero cells. (3) Results: the proteomic analysis by LC\u2013MS\/MS identified the S, N, M, Nsp3, and Nsp7 as putative hemin-binding proteins. Six short sequences in the RBD and 11 in the NTD of the spike were identified by microarray of peptides to interact with Hb and tree motifs in the N protein by in silico analysis to bind with heme. An inhibitory effect in vitro of Hb, hemin, and PpIX at different levels was observed. Strikingly, free Hb at 1mM suppressed viral replication (99%), and its interaction with SARS-CoV-2 was localized into the RBD region of the spike protein. (4) Conclusions: in this study, we identified that (at least) five proteins (S, N, M, Nsp3, and Nsp7) of SARS-CoV-2 recruit Hb\/metabolites. The motifs of the RDB of SARS-CoV-2 spike, which binds Hb, and the sites of the heme bind-N protein were disclosed. In addition, these compounds and PpIX block the virus\u2019s adsorption and replication. Furthermore, we also identified heme-binding motifs and interaction with hemin in N protein and other structural (S and M) and non-structural (Nsp3 and Nsp7) proteins.<\/jats:p>","DOI":"10.3390\/ijms22169035","type":"journal-article","created":{"date-parts":[[2021,8,22]],"date-time":"2021-08-22T21:47:52Z","timestamp":1629668872000},"page":"9035","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["SARS-CoV-2 Proteins Bind to Hemoglobin and Its Metabolites"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4538-3802","authenticated-orcid":false,"given":"Guilherme C.","family":"Lechuga","sequence":"first","affiliation":[{"name":"FIOCRUZ, Center for Technological Development in Health (CDTS), National Institute of Science and Technology for Innovation on Neglected Population Diseases (INCT-IDPN), Rio de Janeiro 21040-900, RJ, Brazil"},{"name":"Laboratory of Celular Ultrastructure, FIOCRUZ, Oswaldo Cruz Institute, Rio de Janeiro 21040-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9216-4306","authenticated-orcid":false,"given":"Franklin","family":"Souza-Silva","sequence":"additional","affiliation":[{"name":"FIOCRUZ, Center for Technological Development in Health (CDTS), National Institute of Science and Technology for Innovation on Neglected Population Diseases (INCT-IDPN), Rio de Janeiro 21040-900, RJ, Brazil"},{"name":"Biology and Heath Science Faculty, Igua\u00e7u University, Nova Igua\u00e7u 26260-045, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3952-7099","authenticated-orcid":false,"given":"Carolina Q.","family":"Sacramento","sequence":"additional","affiliation":[{"name":"FIOCRUZ, Center for Technological Development in Health (CDTS), National Institute of Science and Technology for Innovation on Neglected Population Diseases (INCT-IDPN), Rio de Janeiro 21040-900, RJ, Brazil"},{"name":"Laboratory of Immunopharmacology, FIOCRUZ, Oswaldo Cruz Institute, Rio de Janeiro 21040-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9240-9978","authenticated-orcid":false,"given":"Monique R. O.","family":"Trugilho","sequence":"additional","affiliation":[{"name":"FIOCRUZ, Center for Technological Development in Health (CDTS), National Institute of Science and Technology for Innovation on Neglected Population Diseases (INCT-IDPN), Rio de Janeiro 21040-900, RJ, Brazil"},{"name":"Laboratory of Toxinology, FIOCRUZ, Oswaldo Cruz Institute, Rio de Janeiro 21040-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6562-7571","authenticated-orcid":false,"given":"Richard H.","family":"Valente","sequence":"additional","affiliation":[{"name":"Laboratory of Toxinology, FIOCRUZ, Oswaldo Cruz Institute, Rio de Janeiro 21040-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paloma","family":"Napole\u00e3o-P\u00eago","sequence":"additional","affiliation":[{"name":"FIOCRUZ, Center for Technological Development in Health (CDTS), National Institute of Science and Technology for Innovation on Neglected Population Diseases (INCT-IDPN), Rio de Janeiro 21040-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3104-0983","authenticated-orcid":false,"given":"Suelen S. 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