SARS-CoV-2 induces a broad range of clinical manifestations. Besides the main receptor, ACE2, other putative receptors and co-receptors have been described and could become genuinely relevant to explain the different tropism manifested by new variants. In this study, we propose a biochemical model envisaging the competition for cysteine as a key mechanism promoting the infection and the selection of host receptors. The SARS-CoV-2 infection produces ROS and triggers a massive biosynthesis of proteins rich in cysteine; if this amino acid becomes limiting, glutathione levels are depleted and cannot control oxidative stress. Hence, infection succeeds. A receptor should be recognized as a marker of suitable intracellular conditions, namely the full availability of amino acids except for low cysteine. First, we carried out a comparative investigation of SARS-CoV-2 proteins and human ACE2. Then, using hierarchical cluster protein analysis, we searched for similarities between all human proteins and spike produced by the latest variant, Omicron BA.1. We found 32 human proteins very close to spike in terms of amino acid content. Most of these potential SARS-CoV-2 receptors have less cysteine than spike. We suggest that these proteins could signal an intracellular shortage of cysteine, predicting a burst of oxidative stress when used as viral entry mediators.
Keywords: ACE2; ROS; SARS-CoV-2; SARS-CoV-2 receptor; amino acid availability; cysteine; glutathione; spike.