Unravelling the Mystery of COVID‐19 Pathogenesis: Spike Protein and Cu Can Synergize to Trigger ROS Production

Abstract

The COVID‐19 pandemic has had a devastating impact on global health, highlighting the need to understand how the SARS‐CoV‐2 virus damages the lungs in order to develop effective treatments. Recent research has shown that patients with COVID‐19 experience severe oxidative damage to various biomolecules. We propose that the overproduction of reactive oxygen species (ROS) in SARS‐CoV‐2 infection involves an interaction between copper ions and the virus's spike protein. We tested two peptide fragments, Ac‐ELDKYFKNH‐NH2 (L1) and Ac‐WSHPQFEK‐NH2 (L2), derived from the spike protein of the Wuhan strain and the β variant, respectively, and found that they bind Cu(II) ions and form a three‐nitrogen complexes at lung pH. Our research demonstrates that these complexes trigger the overproduction of ROS, which can break both DNA strands and transform DNA into its linear form. Using A549 cells, we demonstrated that ROS overproduction occurs in the mitochondria, not in the cytoplasm. Our findings highlight the importance of the interaction between copper ions and the virus's spike protein in the development of lung damage and may aid in the development of therapeutic procedures.

Small-Molecule Fluorescent Probes for Binding- and Activity-Based Sensing of Redox-Active Biological Metals

“…254 This sensor was subsequently used to study variations in copper homeostasis in ovarian cancer cells resistant to cisplatin, 279 and to investigate the cellular effects of a copper-binding peptide fragment of the SARS-CoV-2 spike protein. 280 A similar approach was employed in CNSB (143), which comprises coumarin and 4-amino-7sulfamoyl benzoxadiazole (ABSD) fluorophores with the same receptor. 255 The 470 nm emission of coumarin increased slightly with Cu(I) addition, while the 565 nm emission peak corresponding to ABSD decreased in intensity.…”

“…Only the indolinium, to which the copper receptor is directly bound, exhibited a Cu­(I)-dependent emission decrease, whereas the coumarin plays the role of a non-responsive standard . This sensor was subsequently used to study variations in copper homeostasis in ovarian cancer cells resistant to cisplatin, and to investigate the cellular effects of a copper-binding peptide fragment of the SARS-CoV-2 spike protein . A similar approach was employed in CNSB ( 143 ), which comprises coumarin and 4-amino-7-sulfamoyl benzoxadiazole (ABSD) fluorophores with the same receptor .…”