N-ACETYLCYSTEINE (NAC)

N-ACETYLCYSTEINE (NAC)

Viral spike proteins play important roles in the viral entry process, facilitating attachment to cellular receptors and fusion of the viral envelope with the cell membrane. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds to the cellular receptor angiotensin converting enzyme-2 (ACE2) via its receptor-binding domain (RBD). The cysteine residue at position 488, consisting of a disulfide bridge with cysteine 480 is located in an important structural loop at ACE2-binding surface of RBD, and is highly conserved among SARS-related coronaviruses. We showed that the substitution of Cys-488 with alanine impaired pseudotyped SARS-CoV-2 infection, syncytium formation, and cell-cell fusion triggered by SARS-CoV-2 spike expression. Consistently, in vitro binding of RBD and ACE2, spike-mediated cell-cell fusion, and pseudotyped viral infection of VeroE6/TMPRSS2 cells were inhibited by the thiol-reactive compounds N-acetylcysteine (NAC) and a reduced form of glutathione (GSH). Furthermore, we demonstrated that the activity of variant spikes from the SARS-CoV-2 alpha and delta strains were also suppressed by NAC and GSH. (Murae, 2022).

Hydrogen sulfide (H2S) levels at hospital admission may be of importance since this gasotransmitter has been shown to be protective against lung damage through its antiviral, antioxidant, and anti-inflammatory actions. Many COVID-19 cases have been described demonstrating remarkable clinical improvement upon administration of high doses of N-acetylcysteine (NAC). NAC is a renowned pharmacological antioxidant substance acting as a source of cysteine, thereby promoting endogenous glutathione (GSH) biosynthesis as well as generation of sulfane sulfur species when desulfurated to H2S. (Bourgonje, 2021).

RNA viruses need active NF-κB pathway support within host cells in order to replicate. For human coronaviruses (HCoV-229E), suppression of NF-κB significantly reduced the replication rate. Therefore, drugs that inhibit NF-κB activation could potentially reduce viral replication. NAC has been demonstrated to inhibit NF-κB, as well as the replication of human influenza viruses (H5N1, Vietnam/VN1203 strain) in human lung epithelial cells in a dose dependent manner (5 to 15 mM). NAC also reduced the production of pro-inflammatory cytokines (IL-8, CXCL10, CCL5 and IL-6), thus reducing chemotactic migration of monocytes. In addition, NAC has also been showed to inhibit replication of other viruses, such as human immunodeficiency virus (HIV) and respiratory syncytial virus (RSV). This means that, theoretically, NAC has the potential to inhibit SARS-Cov-2 as well because of its ability to negatively regulate NF-κB. (Shi, 2020).

Bourgonje et al. describes the potential role of hydrogen sulfide (H₂S) as a fundamental host defense factor against SARS-CoV-2 infection. Low serum levels of hydrogen sulfide (H₂S) in patients with COVID-19 pneumonia have been shown to be negatively associated with inflammatory biomarkers such as IL-6 and C-reactive protein (CRP), and also associated with a poor prognosis. Endogenous H₂S production can be increased therapeutically by administering N-acetylcysteine (NAC), which can be seen as a potential treatment strategy for COVID-19 patients. NAC may also replenish intracellular reduced glutathione (GSH) pools by providing l-cysteine, a precursor for GSH synthesis. Moreover, NAC has shown the ability to restore the intracellular redox imbalance in vitro experiments. (Avdeev, 2022).

Reference:

(Murae, 2022). Mana Murae, Yoshimi Shimizu, Yuichiro Yamamoto, Asuka Kobayashi, Masumi Houri, Tetsuya Inoue, Takuya Irie, Ryutaro Gemba, Yosuke Kondo, Yoshio Nakano, Satoru Miyazaki, Daisuke Yamada, Akiyoshi Saitoh, Isao Ishii, Taishi Onodera, Yoshimasa Takahashi, Takaji Wakita, Masayoshi Fukasawa, Kohji Noguchi. Biochemical and biophysical research communications 2022 v.597 pp. 30-36:   Severe acute respiratory syndrome coronavirus 2, acetylcysteine, alanine, cell membranes, cysteine, disulfide bonds, giant cells, glutathione, mutation, pathogenicity, research, therapeutics. https://pubag.nal.usda.gov/catalog/7659081

(Bourgonje, 2021). Bourgonje AR, Offringa AK, van Eijk LE, Abdulle AE, Hillebrands JL, van der Voort PHJ, van Goor H, van Hezik EJ. N-Acetylcysteine and Hydrogen Sulfide in Coronavirus Disease 2019. Antioxid Redox Signal. 2021 Mar 25. Retrieved on 03/28/21 online from N-Acetylcysteine and Hydrogen Sulfide in Coronavirus Disease 2019 – PubMed (nih.gov)

(Shi, 2020). Shi Z, Puyo CA. N-Acetylcysteine to Combat COVID-19: An Evidence Review. Ther Clin Risk Manag. 2020;16:1047-1055. Published 2020 Nov 2. doi:10.2147/TCRM.S273700

(Avdeev, 2022). Avdeev SN, Gaynitdinova VV, Merzhoeva ZM, Berikkhanov ZG. N-acetylcysteine for the treatment of COVID-19 among hospitalized patients. J Infect. 2022;84(1):94-118. doi:10.1016/j.jinf.2021.07.003