# The Impact of the S-Adenosylmethionine Analogue Sinefungin on Viral Life Cycles  
[PERSON]  
Department of Medicine, Surgery and Dentistry \"Scuola Medica Saleritana\", University of Salerno, 84081 Baronissi, Italy; [EMAIL_ADDRESS] (F.D. ); [EMAIL_ADDRESS] (N.C.); [EMAIL_ADDRESS] (M.D.P. ); [EMAIL_ADDRESS] (S.R.) C. F. F.  
replication, gene expression, and the ability of the virus to evade the host's immune system. This modification also plays a role in viral integration into the host genome. Additionally, methylation patterns within the viral genome help viruses persist in the host [8]. In this context, [PERSON] et al. performed bisulfite sequencing of the Epstein-Barr virus (EBV) genome, revealing that the viral genome undergoes extensive methylation during the latent phase. In contrast, infectious viral particles showed significant hypomethyllation throughout the genome. In particular, their study highlighted that during the active phase of infection, the repression of EBNA latency genes was associated with hypermethylation in specific promoter regions [9]. Similarly, the E2 gene in the human papillomavirus (HPV) genome harbors CpG islands that serve as methylation loci. Methylation of these regions impairs the transcriptional regulatory function of the E2 protein, disrupting its ability to control the expression of the E6 and E7 oncogenes. This disruption results in the upregulation of E6 and E7, key drivers of HPV-associated oncogenesis [10; 11]. In RNA viruses, methylation is essential to regulating the stability of the viral RNA, protecting it from degradation by host exonucleases. Furthermore, methylation plays a key role in modulating the host immune response by altering the recognition of the viral RNA and consequently evading detection by host immune receptors. This modification is also essential for efficient viral replication and translation. Furthermore, it influences the integration of the viral genome into the host DNA, a critical step in establishing infection and maintaining viral latency [12]. [PERSON] et al. demonstrated that IAV-PR8 mutants with reduced levels of m6A on HA segments showed significantly attenuated pathogenicity, as confirmed by in vivo tests in mice. Notably, only the wild-type virus caused lethality at the same doses tested (10 PFU) [13]. Similarly, [PERSON] et al. and [PERSON] et al. elucidated the impact of cytosine and adenine methylation on the SARS-CoV-2 genome, demonstrating their critical role in regulating viral replication, pathogenicity, and host antiviral responses [14; 15]. Considering the significant impact of methylation modifications on the genome, directing drug development efforts toward targeting methylases holds promising potential. By modulating these enzymes, it may be possible to influence viral replication and pathogenicity and host immune responses, offering new therapeutic strategies to combat viral infections. Sinefungin, a potent inhibitor of SAM-dependent methyltransferases, has attracted considerable attention as a valuable tool in the study of methylation processes [16]. By interrupting the activity of methyltransferases, sinefungin offers a promising approach to modulating viral pathogenesis. Studies on the antiviral activity of sinefungin are limited. It has been shown to exhibit antiviral effects against Vaccinia virus and feline immunodeficiency virus-1 (FIV-1) [17; 18]. Due to the distinct characteristics of these viruses, the observed antiviral activity suggests the potential for sinefungin to target a broader range of viral pathogens. In this context, we evaluated the antiviral activity of sinefungin against Herpes Simplex Virus 1 (HSV-1) and SARS-CoV-2, including its variants, due to the significant public health impact of these viruses. HSV-1, a DNA virus, is known for its ability to establish lifelong latency, while SARS-CoV-2 and its variants, rapidly mutating RNA viruses, have caused a global pandemic, with persistent therapeutic challenges [19; 20].