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Abstract When it is in the template RNA, the naturally occurring m1A epitranscriptomic RNA modification was recently reported to be able to stop the RNA polymerization reaction catalyzed by the RNA dependent RNA polymerase (RdRp) of SARS-CoV-2. In this report, we report that m1A via its triphosphate form (m1ATP) can be incorporated into RNA by the same RdRp. These two findings point a new direction for antiviral drug development based on m1A for combatting COVID-19. More broadly, it is possible that the large pool of epigenetic RNA as well as DNA modifications could serve as a treasury for drug discovery aimed at combating various infectious and other diseases.
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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 (m5C),N6‐methyladenosine (m6A),N1‐methyladenosine (m1A) andN3‐methylcytosine (m3C) on the activity of SARS‐CoV‐2 replication complex (SC2RC). We found that Ψ, m5C, m6A and m3C had little effect, whereas m1A inhibited the enzyme. Both m1A and m3C disrupt canonical base pairing, but they had different effects. The fact that m1A inhibits SC2RC implies that the modification can be difficult to detect. This fact also implies that individuals with upregulated m1A including cancer, obesity and diabetes patients might have milder symptoms. However, this contradicts clinical observations. Relevant discussions are provided.
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- Award ID(s):
- 1954041
- PAR ID:
- 10402873
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- ChemBioChem
- Volume:
- 24
- Issue:
- 8
- ISSN:
- 1439-4227
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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