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SARS-COV-2 PROTEINS BIND TO HEMOGLOBIN AND ITS METABOLITES
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Abstract
(1) Background: coronavirus disease 2019 (COVID-19), caused by severe acute respira tory 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–MS/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–MS/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’s 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.
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