Convergent evolution of viral nucleases targeting cyclic dinucleotides

Poxviruses, African swine fever virus (ASFV), and bacteriophages have independently evolved nucleases that degrade cyclic dinucleotides (CDNs), which are critical second messengers that mediate antiviral responses. This Pearl synthesizes recent advancements in our understanding of viral CDN-degrading nucleases and emphasizes three key themes. First, there is the conservation of CDN signaling mechanisms across different biological domains. Second, we observe the diverse structural adaptations of viral nucleases for CDN degradation. Finally, structural protein folds are conserved, allowing for functional replacements across species. Additionally, we discuss the therapeutic potential of targeting these nucleases with resistant CDN analogues and through structure-guided drug discovery. This convergence in viral immune evasion strategies provides valuable insights into the development of broad-spectrum antiviral therapies and offers new opportunities for enhancing immune responses in therapeutic contexts.