Discovery of a Baloxavir-Inspired Endonuclease InhibitorThat Prevents Herpes Simplex Virus 1 Replication in CellCulture and In Vivo
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 appr...
| Autores: | , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Universidad Autónoma de Madrid |
| Repositorio: | Biblos-e Archivo. Repositorio Institucional de la UAM |
| Idioma: | inglés |
| OAI Identifier: | oai:dnet:biblosearchi::44e1b927c1005824afbc9387e8387750 |
| Acceso en línea: | https://hdl.handle.net/10486/764840 https://dx.doi.org/10.1002/advs.202508006 |
| Access Level: | acceso abierto |
| Palabra clave: | Antiviral drug baloxavir DNA packaging herpesvirus HSV metalloenzymes nuclease Biología y Biomedicina / Biología |
| Sumario: | 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 |
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