Dataset Information

Effects of Epitranscriptomic RNA Modifications on the Catalytic Activity of the SARS-CoV-2 Replication Complex.

ABSTRACT: SARS-CoV-2 causes individualized symptoms. Many reasons have been given. We propose that an individual's epitranscriptomic system could be responsible as well. The viral RNA genome can be subject to epitranscriptomic modifications, which can be different for different individuals, and thus epitranscriptomics can affect many events including RNA replication differently. In this context, we studied the effects of modifications including pseudouridine (Ψ), 5-methylcytosine (m⁵ C), N6-methyladenosine (m⁶ A), N1-methyladenosine (m¹ A) and N3-methylcytosine (m³ C) on the activity of SARS-CoV-2 replication complex (SC2RC). We found that Ψ, m⁵ C, m⁶ A and m³ C had little effect, whereas m¹ A inhibited the enzyme. Both m¹ A and m³ C disrupt canonical base pairing, but they had different effects. The fact that m¹ A inhibits SC2RC implies that the modification can be difficult to detect. This fact also implies that individuals with upregulated m¹ A including cancer, obesity and diabetes patients might have milder symptoms. However, this contradicts clinical observations. Relevant discussions are provided.

SUBMITTER: Apostle A

PROVIDER: S-EPMC10121919 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Effects of Epitranscriptomic RNA Modifications on the Catalytic Activity of the SARS-CoV-2 Replication Complex.

Apostle Alexander A Yin Yipeng Y Chillar Komal K Eriyagama Adikari M D N AMDN Arneson Reed R Burke Emma E Fang Shiyue S Yuan Yinan Y

Chembiochem : a European journal of chemical biology 20230322 8

SARS-CoV-2 causes individualized symptoms. Many reasons have been given. We propose that an individual's epitranscriptomic system could be responsible as well. The viral RNA genome can be subject to epitranscriptomic modifications, which can be different for different individuals, and thus epitranscriptomics can affect many events including RNA replication differently. In this context, we studied the effects of modifications including pseudouridine (Ψ), 5-methylcytosine (m<sup>5</sup> C), N6-met ...[more]

PMID: 36752976

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Project description:Here, we screened steroid compounds to obtain a drug expected to block host inflammatory responses and Middle East respiratory syndrome coronavirus (MERS-CoV) replication. Ciclesonide, an inhaled corticosteroid, suppressed the replication of MERS-CoV and other coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), in cultured cells. The 90% effective concentration (EC90) of ciclesonide for SARS-CoV-2 in differentiated human bronchial tracheal epithelial cells was 0.55 μM. Eight consecutive passages of 43 SARS-CoV-2 isolates in the presence of ciclesonide generated 15 resistant mutants harboring single amino acid substitutions in nonstructural protein 3 (nsp3) or nsp4. Of note, ciclesonide suppressed the replication of all these mutants by 90% or more, suggesting that these mutants cannot completely overcome ciclesonide blockade. Under a microscope, the viral RNA replication-transcription complex in cells, which is thought to be detectable using antibodies specific for nsp3 and double-stranded RNA, was observed to fall in the presence of ciclesonide in a concentration-dependent manner. These observations indicate that the suppressive effect of ciclesonide on viral replication is specific to coronaviruses, highlighting it as a candidate drug for the treatment of COVID-19 patients.IMPORTANCE The outbreak of SARS-CoV-2, the cause of COVID-19, is ongoing. New and effective antiviral agents that combat the disease are needed urgently. Here, we found that an inhaled corticosteroid, ciclesonide, suppresses the replication of coronaviruses, including betacoronaviruses (murine hepatitis virus type 2 [MHV-2], MERS-CoV, SARS-CoV, and SARS-CoV-2) and an alphacoronavirus (human coronavirus 229E [HCoV-229E]), in cultured cells. Ciclesonide is safe; indeed, it can be administered to infants at high concentrations. Thus, ciclesonide is expected to be a broad-spectrum antiviral drug that is effective against many members of the coronavirus family. It could be prescribed for the treatment of MERS and COVID-19.

Dataset Information

Effects of Epitranscriptomic RNA Modifications on the Catalytic Activity of the SARS-CoV-2 Replication Complex.

Publications

Effects of Epitranscriptomic RNA Modifications on the Catalytic Activity of the SARS-CoV-2 Replication Complex.

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