How the Competition for Cysteine May Promote Infection of SARS-CoV-2 by Triggering Oxidative Stress

Abstract

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.

Figure 1

Schematic representation of the biochemical model proposed to describe how the binding to a receptor poor of Cys can drive the viral entry into a cellular milieu suitable for viral replication.

Figure 2

Similarities with spike of 32 proteins of interest. The similarity is expressed as the distance from spike, by a scale of values ranging from 1 (no similarity) to 0 (identical proteins). (A) A total of 14 proteins were more similar to spike than ACE2 in the analysis without Cys. (B) A total of 18 proteins were close but slightly less similar to spike than ACE2 in the analysis without Cys. Many similarities were confirmed by four algorithms (red-outlined bars—validated).