Dual effect of nitric oxide on SARS-CoV replication: Viral RNA production and palmitoylation of the S protein are affected

Abstract

Nitric oxide is an important molecule playing a key role in a broad range of biological process such as neurotransmission, vasodilatation and immune responses. While the anti-microbiological properties of nitric oxide-derived reactive nitrogen intermediates (RNI) such as peroxynitrite, are known, the mechanism of these effects are as yet poorly studied. Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) belongs to the family Coronaviridae, was first identified during 2002-2003. Mortality in SARS patients ranges from between 6 to 55%. We have previously shown that nitric oxide inhibits the replication cycle of SARS-CoV in vitro by an unknown mechanism. In this study, we have further investigated the mechanism of the inhibition process of nitric oxide against SARS-CoV. We found that peroxynitrite, an intermediate product of nitric oxide in solution formed by the reaction of NO with superoxide, has no effect on the replication cycle of SARS-CoV, suggesting that the inhibition is either directly effected by NO or a derivative other than peroxynitrite. Most interestingly, we found that NO inhibits the replication of SARS-CoV by two distinct mechanisms. Firstly, NO or its derivatives cause a reduction in the palmitoylation of nascently expressed spike (S) protein which affects the fusion between the S protein and its cognate receptor, angiotensin converting enzyme 2. Secondly, NO or its derivatives cause a reduction in viral RNA production in the early steps of viral replication, and this could possibly be due to an effect on one or both of the cysteine proteases encoded in Orf1a of SARS-CoV.

Roles of the antioxidant properties of icariin and its phosphorylated derivative in the protection against duck virus hepatitis

“…It was reported that viral infection increases iNOS mRNA expression and NO production. In turn, NO promotes viral replication in infected cells [20][21][22][23]. In our study, at 54 h after exposure to DHV-1, iNOS and MDA levels were significantly greater in the VC group than in BC group.…”

A radical form of nitric oxide inhibits porcine circovirus type 2 replication in vitro

“…Interestingly, A previous report revealed that NO • released from SNP plus ascorbate could delay and block rabies replication in neuroblastoma cells, while viral replication was not influenced by NO + generated from SNP alone, and this data was similar to our study [26]. The mechanisms involved in the antiviral properties of NO were partially confirmed in previous studies, indicating that NO played an important role in regulation of viral protease [27], innate immunity of the host [11], as well as viral protein and nucleic acid synthesis [28]. For PCV2, we found that NO generated from SNP plus VC inhibited synthesis of infectious virions by reducing the number of viral infected cells and by downregulation of viral titers and viral DNA copies.…”

Post-Translational Modifications of Coronavirus Proteins: Roles and Function

“…However, unlike MHV S protein, palmitoylation of SARS-CoV S protein was not required for S-M interaction [76]. Interestingly, treatment of nitric oxide or its derivatives led to a reduction in the palmitoylation of SARS-CoV S protein, which affected its binding to the cognate receptor ACE2 [77]. The S protein of the Alphacoronavirus TGEV is also modified by palmitoylation, and inhibition of palmitoylation by 2-bromopalmitate treatment reduced TGEV replication in cell culture [78].…”