- The E protein of SARS-CoV (genetically related to SARS-CoV-2) consists of 76–109 amino acids, ranging in size from 8.4 to 12 kDa. Its primary and secondary structures have a short, hydrophilic amine terminus group of 7–12 amino acids followed by a hydrophobic 25 amino acid transmembrane domain which ends in a hydrophilic carboxyl group terminus . The SARS-CoV-2 E protein includes a triple cysteine motif (NH2- … L-Cys-A-Y-Cys-Cys-N … -COOH) after the transmembrane domain which interacts with a similar motif from S protein terminal C- (NH2- … S-Cys-G-S-Cys-Cys-K … -COOH) . Both motifs interact through disulfide bonds , and NAC may cleave them. This would decrease SARS-CoV-2 infectivity.
- In vitro studies have shown NAC to decrease angiotensin II bonds to angiotensin II type 1 receptor in a dose-dependent manner . In the COVID-19 context, NAC could block excessive production of angiotensin II, which cannot be cleaved to angiotensin 1–7 by ACE2. This may decrease pulmonary disease severity.
- In vitro and clinical studies have shown NAC to block ACE. In one experiment isosorbide dinitrate (vasodilator activity) was administered to six male participants for 48 h, but at 24 h NAC was added (2 g intravenously [iv.] followed by 5 mg/kg/h). Angiotensin II plasma concentrations increased during the first 24 h of isosorbide dinitrate administration but just 2 h after NAC initiation they had decreased from 28 ± 4 to 14 ± 2 ng/l (p < 0.05) . This suggests that, by blocking ACE, NAC may provide protection from the deleterious effects of angiotensin II, a potentially useful activity in a SARS-CoV-2 infection scenario.
- The oxidative stress environment created by cytokine storm syndrome and production of reactive oxygen species (ROS) may be attenuated by NAC’s antioxidant effect . Also, the SARS-CoV-2 immunopathology may be similar to that of SARS-CoV, which generates an immune response involving diverse pro-inflammatory cytokines (IL-1, IL-2, IL-4, TNF and IFNs). The IFNs are classified in type-I (IFN-α and β), -II (IFN-γ) and -III. Type-I IFNs are suppressed during SARS-CoV infection due to impairment of signal transducer and activator of transcription 1, which ultimately antagonizes IFN. This complex mechanism may also generate delayed IFN response due to cytokine storm syndrome during SARS-CoV-2 infection, possibly explaining COVID-19 pathology. NAC may amplify the signaling functions of toll-like receptor 7 and mitochondrial antiviral signaling protein in restoring type-I IFN production during SARS-CoV-2 infection .
- NAC has been shown to restore platelet GSH reserves (in a murine model) which in turn can prevent protein glycosylation by methylglyoxal, a pathologic mechanism in diabetic patients . The SARS-CoV-2 S glycoprotein differs from that of SARS-CoV in that it gains new glycosylation sites (NGTK, NFTI, NLTT and NTSN), allowing SARS-CoV-2 to enter the host cell . Administration of NAC could prevent additional glycosylation events in SARS-CoV-2, thus inhibiting its infectivity and any associated pathologies.
- In a recent study the NF-κB was described as a mediator of SARS-CoV-2 pulmonary pathology since it triggers the production of numerous pro-inflammatory cytokines. This process generates macrophage and neutrophil infiltration, both of which cause irreparable damage to pulmonary epithelium cells. NAC was shown to inhibit NF-κB activation in an in vitro influenza (A and B) model ; the proposed mechanism is restauration of thiol pools which may allow ROS scavenging. This is relevant because recent clinical experience has shown that severity of COVID-19 clinical manifestations might be associated with decreased GSH levels and the consequent increased ROS production. Severe COVID-19 cases would therefore probably manifest lower GSH levels, higher ROS levels and greater redox status (ROS/GSH ratio) than milder cases .
- In the context of influenza virus infection, NAC administration (100 mg/kg continuous iv. infusion daily for 3 days) was reported to promote clinical improvement in a woman with H1N1 influenza pneumonia; oseltamivir was also employed during treatment . However, other studies have found no beneficial in vitro or vivo effects with NAC administration . NAC (600 mg twice daily) has also been reported to attenuate influenza symptoms in patients ≥65-years old with chronic-degenerative diseases .
References: or Cited By:
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