A cap-dependent endonuclease inhibitor acts as a potent antiviral agent against La Crosse virus infection.
Gespeichert in:
| Titel: | A cap-dependent endonuclease inhibitor acts as a potent antiviral agent against La Crosse virus infection. |
|---|---|
| Autoren: | Konishi K; Laboratory for Drug Discovery & Disease Research, Shionogi & Co., Ltd., Osaka, Japan.; Division of Anti-Virus Drug Research, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan., Taoda Y; Laboratory for Medicinal Chemistry Research, Shionogi & Co., Ltd., Osaka, Japan., Igarashi M; Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan.; International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan., Shishido T; Laboratory for Drug Discovery & Disease Research, Shionogi & Co., Ltd., Osaka, Japan., Yasuo K; Laboratory for Medicinal Chemistry Research, Shionogi & Co., Ltd., Osaka, Japan., Hall WW; International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan.; National Virus Reference Laboratory, School of Medicine, University College Dublin, Dublin, Ireland.; Global Virus Network, Baltimore, Maryland, USA.; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan., Orba Y; Division of Anti-Virus Drug Research, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan.; International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan.; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan.; Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan.; One Health Research Center, Hokkaido University, Sapporo, Japan., Sawa H; Division of Anti-Virus Drug Research, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan.; International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan.; Global Virus Network, Baltimore, Maryland, USA.; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan.; One Health Research Center, Hokkaido University, Sapporo, Japan., Sasaki M; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan.; Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan., Sato A; Laboratory for Drug Discovery & Disease Research, Shionogi & Co., Ltd., Osaka, Japan.; Division of Anti-Virus Drug Research, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan.; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan. |
| Quelle: | Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2025 Sep 03; Vol. 69 (9), pp. e0018625. Date of Electronic Publication: 2025 Jul 23. |
| Publikationsart: | Journal Article |
| Sprache: | English |
| Info zur Zeitschrift: | Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 0315061 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-6596 (Electronic) Linking ISSN: 00664804 NLM ISO Abbreviation: Antimicrob Agents Chemother Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Washington, American Society for Microbiology |
| MeSH-Schlagworte: | Antiviral Agents*/pharmacology , La Crosse virus*/drug effects , La Crosse virus*/enzymology , La Crosse virus*/genetics , Encephalitis, California*/drug therapy , Encephalitis, California*/virology , Pyridones*/pharmacology , Endonucleases*/antagonists & inhibitors , Endonucleases*/metabolism , Endonucleases*/genetics , Enzyme Inhibitors*/pharmacology, Animals ; Mice ; Humans ; Pyrazines/pharmacology ; Viral Load/drug effects ; Amides/pharmacology ; Vero Cells ; Ribavirin/pharmacology ; Virus Replication/drug effects ; Chlorocebus aethiops |
| Abstract: | Competing Interests: All experiments reported in this paper were financially supported by Shionogi & Co., Ltd. K.K., Y.T., K.Y., T.S., and A.S. are employees of Shionogi & Co., Ltd. The remaining authors declare no competing interests. La Crosse virus (LACV) infection, the causative agent of La Crosse encephalitis, can lead to severe neurological symptoms and sequelae, particularly in children. Despite annual reports of neurologically symptomatic cases, no effective treatment has yet been established. Bunyaviruses, including LACV, utilize a cap-snatching mechanism for transcription, with a cap-dependent endonuclease (CEN) serving as a promising target for antiviral treatment. Specifically, we now demonstrate that a CEN inhibitor, carbamoyl pyridone carboxylic acid (CAPCA)-1, exhibits potent anti-LACV activity in vitro and in vivo . CAPCA-1 exhibited 50% effective concentration values below 1 µM in neuronal and non-neuronal cells, demonstrating a higher in vitro activity than the nucleoside analogs, ribavirin and favipiravir. Multiple passages of LACV in the presence of CAPCA-1 produced numerous amino acid mutations in the CEN active site. Notably, using a lethal infection model in mice, CAPCA-1 treatment reduced viral loads in the brain and extended the survival rate of LACV-infected mice. These findings highlight the potential of CEN inhibitors as treatment options for La Crosse encephalitis. |
| References: | IUCrJ. 2024 May 1;11(Pt 3):374-383. (PMID: 38656310) Antiviral Res. 2017 Oct;146:1-11. (PMID: 28818572) Am J Trop Med Hyg. 2024 Mar 26;110(5):850-855. (PMID: 38531108) Antiviral Res. 2019 Jul;167:1-5. (PMID: 30951731) Trends Microbiol. 2020 Apr;28(4):293-303. (PMID: 31948728) Am J Epidemiol. 1965 Mar;81:245-53. (PMID: 14261030) PLoS Negl Trop Dis. 2021 Jul 2;15(7):e0009553. (PMID: 34214091) Am J Trop Med Hyg. 2021 Jul 19;105(3):807-812. (PMID: 34280142) Antimicrob Agents Chemother. 1989 Nov;33(11):2009-11. (PMID: 2610511) Viruses. 2024 Apr 18;16(4):. (PMID: 38675972) J Neuroinflammation. 2018 Nov 15;15(1):315. (PMID: 30442185) Pediatr Infect Dis J. 2011 Oct;30(10):860-5. (PMID: 21544005) Antimicrob Agents Chemother. 2022 Jun 21;66(6):e0029222. (PMID: 35652314) J Antimicrob Chemother. 2020 Nov 1;75(11):3189-3193. (PMID: 32766680) Curr Med Chem. 2010;17(32):3874-908. (PMID: 20858214) Sci Rep. 2018 Jun 25;8(1):9633. (PMID: 29941893) J Clin Microbiol. 2005 Apr;43(4):1885-9. (PMID: 15815013) J Virol. 2015 Oct 14;90(1):189-205. (PMID: 26468541) J Virol. 2024 Oct 22;98(10):e0106924. (PMID: 39303014) Nat Microbiol. 2021 Nov;6(11):1398-1409. (PMID: 34675384) ACS Med Chem Lett. 2023 Mar 30;14(4):506-513. (PMID: 37077387) Cytokine. 2005 Sep 21;31(6):454-8. (PMID: 16129617) N Engl J Med. 2001 Mar 15;344(11):801-7. (PMID: 11248155) Antimicrob Agents Chemother. 2007 Sep;51(9):3168-76. (PMID: 17606691) PLoS Pathog. 2024 Sep 30;20(9):e1012574. (PMID: 39348391) Proc Natl Acad Sci U S A. 2022 Sep 6;119(36):e2206104119. (PMID: 36037386) Pediatrics. 1997 Feb;99(2):261-7. (PMID: 9024460) PLoS Pathog. 2010 Sep 16;6(9):e1001101. (PMID: 20862319) Antiviral Res. 2018 Dec;160:48-54. (PMID: 30339848) Antimicrob Agents Chemother. 2020 May 21;64(6):. (PMID: 32284379) Antiviral Res. 2018 Dec;160:109-117. (PMID: 30316915) Clin Drug Investig. 2018 Dec;38(12):1189-1196. (PMID: 30288682) Viruses. 2022 Sep 28;14(10):. (PMID: 36298693) Antimicrob Agents Chemother. 2002 Apr;46(4):977-81. (PMID: 11897578) J Virol. 2024 Nov 19;98(11):e0030024. (PMID: 39382324) N Engl J Med. 2018 Sep 6;379(10):913-923. (PMID: 30184455) J Neuroinflammation. 2019 Nov 18;16(1):229. (PMID: 31739796) Immunity. 2013 Apr 18;38(4):705-16. (PMID: 23499490) |
| Grant Information: | JPMJMS2025 Japan Science and Technology Agency; JP223fa627005, JP23wm0125008 Japan Agency for Medical Research and Development |
| Contributed Indexing: | Keywords: La Crosse virus; antivirals; bunyaviruses; cap-dependent endonuclease |
| Substance Nomenclature: | 0 (Antiviral Agents) 0 (Pyridones) EC 3.1.- (Endonucleases) 0 (Pyrazines) EW5GL2X7E0 (favipiravir) 0 (Enzyme Inhibitors) 0 (Amides) 49717AWG6K (Ribavirin) |
| Entry Date(s): | Date Created: 20250723 Date Completed: 20250903 Latest Revision: 20250905 |
| Update Code: | 20250905 |
| PubMed Central ID: | PMC12406681 |
| DOI: | 10.1128/aac.00186-25 |
| PMID: | 40698821 |
| Datenbank: | MEDLINE |
Nájsť tento článok vo Web of Science | Abstract: | Competing Interests: All experiments reported in this paper were financially supported by Shionogi & Co., Ltd. K.K., Y.T., K.Y., T.S., and A.S. are employees of Shionogi & Co., Ltd. The remaining authors declare no competing interests.<br />La Crosse virus (LACV) infection, the causative agent of La Crosse encephalitis, can lead to severe neurological symptoms and sequelae, particularly in children. Despite annual reports of neurologically symptomatic cases, no effective treatment has yet been established. Bunyaviruses, including LACV, utilize a cap-snatching mechanism for transcription, with a cap-dependent endonuclease (CEN) serving as a promising target for antiviral treatment. Specifically, we now demonstrate that a CEN inhibitor, carbamoyl pyridone carboxylic acid (CAPCA)-1, exhibits potent anti-LACV activity in vitro and in vivo . CAPCA-1 exhibited 50% effective concentration values below 1 µM in neuronal and non-neuronal cells, demonstrating a higher in vitro activity than the nucleoside analogs, ribavirin and favipiravir. Multiple passages of LACV in the presence of CAPCA-1 produced numerous amino acid mutations in the CEN active site. Notably, using a lethal infection model in mice, CAPCA-1 treatment reduced viral loads in the brain and extended the survival rate of LACV-infected mice. These findings highlight the potential of CEN inhibitors as treatment options for La Crosse encephalitis. |
|---|---|
| ISSN: | 1098-6596 |
| DOI: | 10.1128/aac.00186-25 |