Disulfide Bonds Play a Critical Role in the Structure and Function of the Receptor-binding Domain of the SARS-CoV-2 Spike Antigen

Hyperglycemia and Loss of Redox Homeostasis in COVID-19 Patients

“…Our results show that the level of thiols in plasma from patients with COVID-19 was decreased in moderate and severe cases. This result is similar to the one found in another study where it was demonstrated that COVID-19 patients' course with low levels of thiols and that their level can even be a marker that reflects the gradual increase in the severity of the infection [62]. This result is very important because different investigations have reported that the treatment with agents capable of elevating the reducing thiol groups such as GSH, allicin, garlic and N-acetylcysteine, can restore the homeostasis of thiols and decrease the degree of viral infection increasing the TAC and decreasing the LPO in COVID-19 patients [63].…”

The function of SARS-CoV-2 spike protein is impaired by disulfide-bond disruption with mutation at cysteine-488 and by thiol-reactive N-acetyl-cysteine and glutathione

“…1 G and H, respectively). Since the disulfide bridge between Cys-488 and Cys-480 is critical for ACE2-interacting loop structure [ 22 ], mutation at Cys-488 might disrupt structural stability around ACE2-interacting loop essential for spike function.…”

“…Star et al performed deep mutational analysis of RBD using a yeast display system, suggesting possible impact of Cys-488 mutations on the ACE2-binding ability [ 34 ]. The possible therapeutic efficacy of NAC on COVID-19 has been suggested [ 26 ], and the most recent papers by Manček‐Keber et al and Grishin et al consistently reported that thiol-reactive compounds would target spike protein, and disruptions of Cys-480 and Cys-488 diminish the fusogenic activity of the SARS-CoV-2 spike [ 21 , 22 ]. Additionaly, our independent study here showed that RBD-ACE2 binding-mediated functions of variant spike proteins were directly suppressed by thiol-reactive agents.…”

“…The conformational flexibility and stability of viral proteins are affected by intramolecular and intermolecular disulfide bridges [ 15 ], and viral envelope protein-mediated virus attachment/cell membrane fusion is thought to depend on a thiol/disulfide balance within the viral surface complex [ 16 , 17 ]. Although the redox insensitivity of the SARS-CoV spike protein has been previously reported [ 18 ], the functional importance of the disulfide bridge in SARS-CoV and SARS-CoV-2 RBDs has been suggested using both computational and experimental approaches [ [19] , [20] , [21] , [22] ]. The disulfide bridge Cys-480-Cys-488 in RBD appears to contribute to the structural stability of the β-sheet loop motif [ 23 , 24 ], and discussed the possible therapeutic effects of thiol-based drugs on COVID-19 [ 19 , 25 , 26 ].…”

Photodynamic Inactivation of Human Coronaviruses

“…Our observation of reduced electrophoretic mobility of SARS-CoV-2 S from purified lentiviruses following exposure to photoactivated PhytoQuin is suggestive of aggregation or cross-linking of these viral glycoproteins (Figure 5B,C). CoV S proteins contain numerous cysteine residues in their ectodomains, where the majority form disulfide bonds to support protein structure and function [39][40][41][42][43][44]. Cysteines of S proteins may be oxidized via photoactivation to form inter-protein linkages similar to heterodimeric protein crosslinking observed in vitro with the PS rose bengal [45].…”