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The Tautomeric State of N4-Hydroxycytidine within Base-Paired RNA

Bessi et al., ACS Central Science, doi:10.1021/acscentsci.4c00146
Apr 2024  
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In Vitro study showing that NHC, the active form of molnupiravir, can base pair with both G and A in two different tautomeric forms. This ambiguous base pairing enables NHC to induce mutations in the viral RNA. However, it raises the possibility that NHC could also be incorporated into host cell RNA and DNA, potentially causing unwanted mutations in human cells as well. The significant destabilization of RNA duplexes caused by NHC incorporation, especially the impact on neighboring base pairs, suggests it could disrupt the structure and function of not just viral RNA, but any RNA it gets incorporated into, including human cellular RNA involved in normal physiological processes. The fact that NHC:G pairs are more destabilizing than NHC:A pairs and slow down RNA polymerase more also hints that NHC could have complex, sequence-dependent effects that may be hard to predict and control when it comes to off-target incorporation in human cells.
Concerns have been raised that the mutagenic mechanism of action may create dangerous variants or cause cancer1-9. Multiple analyses have identified variants potentially created by molnupiravir10-13.
Bessi et al., 25 Apr 2024, peer-reviewed, 7 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperMolnupiravirAll
The Tautomeric State of N4-Hydroxycytidine within Base-Paired RNA
Irene Bessi, Carina Stiller, Till Schroeder, Benedikt Schäd, Matthias Grüne, Julia Dietzsch, Claudia Höbartner
ACS Central Science, doi:10.1021/acscentsci.4c00146
Antiviral nucleoside analogues (e.g., Molnupiravir, Remdesivir) played key roles in the treatment of COVID-19 by targeting SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). The nucleoside of Molnupiravir, N 4 -hydroxycytidine (NHC), exists in two tautomeric forms that pair either with G or A within the RdRp active site, causing an accumulation of viral RNA mutations during replication. Detailed insights into the tautomeric states within base pairs and the structural influence of NHC in RNA are still missing. In this study, we investigate the properties of NHC:G and NHC:A base pairs in a self-complementary RNA duplex by UV thermal melting and NMR spectroscopy using atom-specifically 15 N-labeled versions of NHC that were incorporated into oligonucleotides by solid-phase synthesis. NMR analysis revealed that NHC forms a Watson-Crick base pair with G via its amino form, whereas two equally populated conformations were detected for the NHC:A base pair: a weakly hydrogen-bonded Watson-Crick base pair with NHC in the imino form and another conformation with A shifted toward the minor groove. Moreover, we found a variable influence of NHC:G and NHC:A base pairs on the neighboring duplex environment. This study provides conclusive experimental evidence for the existence of two tautomeric forms of NHC within RNA base pairs.
Author Contributions ∥ I.B. and C.S. contributed equally. The manuscript was written through contributions of all authors. Notes The authors declare no competing financial interest.
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