Host and viral proteins involved in SARS‐CoV‐2 infection differentially bind heme

In most severe cases, SARS‐CoV‐2‐induced autoimmune reactions have been associated with hemolytic complications. Hemolysis‐derived heme from ruptured red blood cells has been shown to trigger a variety of fatal proinflammatory and procoagulant effects, which might deteriorate the progression of COVID‐19. In addition, the virus itself can induce proinflammatory signals via the accessory protein 7a. Direct heme binding to the SARS‐CoV‐2 protein 7a ectodomain and other COVID‐19‐related proteins has been suggested earlier. Here, we report the experimental analysis of heme binding to the viral proteins spike glycoprotein, protein 7a as well as the host protein ACE2. Thus, protein 7a chemical synthesis was established, including an in‐depth analysis of the three different disulfide‐bonded isomers. Surface plasmon resonance spectroscopy and in silico studies confirm a transient, biphasic binding behavior, and heme‐binding affinities in the nano‐ to low micromolar range. These results confirm the presence of the earlier identified heme‐binding motifs and emphasize the relevance for consideration of labile heme in preexisting or SARS‐CoV‐2‐induced hemolytic conditions in COVID‐19 patients.