Discovery of a Baloxavir‐Inspired Endonuclease Inhibitor That Prevents Herpes Simplex Virus 1 Replication in Cell Culture and In Vivo

Current herpesvirus treatments targeting the viral DNA polymerase are limited by toxicities and drug resistance. Novel compounds inhibiting the nuclease activity of the herpes simplex virus 1 (HSV‐1) terminase complex, required for viral genome packaging, have been identified. Among them, LN‐7 demonstrates efficacy against HSV‐1 in cell culture and animal models (mice), emerging as a “first‐in‐class” antiviral drug candidate. Abstract Herpes simplex viruses (HSV‐1 and HSV‐2) are highly prevalent and contagious, causing lifelong infections that cannot be eradicated with current therapies. Acyclovir and other viral DNA polymerase inhibitors are effective antiviral agents for treating HSV infections. However, despite the recent approval of pritelivir and amenamevir (helicase–primase complex inhibitors), drug resistance is still a major threat to therapeutic success. This research focuses on developing new antiviral strategies against HSV‐1 by targeting the pUL15 endonuclease, a component of the viral packaging motor/terminase complex, using substituted polycyclic pyridones derived from baloxavir acid. Several compounds display low micromolar IC50 values in enzymatic assays. Among them, the prioritized compound, LN‐7, shows a 50% effective concentration (EC50) of 2.8 ± 1.1 µm in antiviral assays and favorable pharmacokinetic properties in rats. LN‐7 demonstrates antiviral efficacy in infected mice, while exhibiting fewer clinical signs compared to controls. Overall, LN‐7 emerges as a promising lead for treating herpesvirus infections and is therefore a first‐in‐class drug candidate targeting HSV genome packaging. Current herpesvirus treatments targeting the viral DNA polymerase are limited by toxicities and drug resistance. Novel compounds inhibiting the nuclease activity of the herpes simplex virus 1 (HSV-1) terminase complex, required for viral genome packaging, have been identified. Among them, LN-7 demonstrates efficacy against HSV-1 in cell culture and animal models (mice), emerging as a “first-in-class” antiviral drug candidate. Abstract Herpes simplex viruses (HSV-1 and HSV-2) are highly prevalent and contagious, causing lifelong infections that cannot be eradicated with current therapies. Acyclovir and other viral DNA polymerase inhibitors are effective antiviral agents for treating HSV infections. However, despite the recent approval of pritelivir and amenamevir (helicase–primase complex inhibitors), drug resistance is still a major threat to therapeutic success. This research focuses on developing new antiviral strategies against HSV-1 by targeting the pUL15 endonuclease, a component of the viral packaging motor/terminase complex, using substituted polycyclic pyridones derived from baloxavir acid. Several compounds display low micromolar IC 50 values in enzymatic assays. Among them, the prioritized compound, LN-7, shows a 50% effective concentration (EC 50 ) of 2.8 ± 1.1 µ m in antiviral assays and favorable pharmacokinetic properties in rats. LN-7 demonstrates antiviral efficacy in infected mice, while exhibiting fewer clinical signs compared to controls. Overall, LN-7 emerges as a promising lead for treating herpesvirus infections and is therefore a first-in-class drug candidate targeting HSV genome packaging. Advanced Science, Volume 12, Issue 42, November 13, 2025.