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Potent inhibition of arenavirus infection by a novel fusion inhibitor.
Gowen, Brian B; Naik, Shibani; Westover, Jonna B; Brown, Eric R; Gantla, Vidyasagar R; Fetsko, Alexandra; Dagley, Ashley L; Blotter, Dallan J; Anderson, Nicole; McCormack, Ken; Henkel, Greg.
Afiliación
  • Gowen BB; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA. Electronic address: brian.gowen@usu.edu.
  • Naik S; Arisan Therapeutics, San Diego, CA, USA.
  • Westover JB; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA.
  • Brown ER; Arisan Therapeutics, San Diego, CA, USA.
  • Gantla VR; Arisan Therapeutics, San Diego, CA, USA.
  • Fetsko A; Arisan Therapeutics, San Diego, CA, USA.
  • Dagley AL; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA.
  • Blotter DJ; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA.
  • Anderson N; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA.
  • McCormack K; Arisan Therapeutics, San Diego, CA, USA. Electronic address: kenm@arisanthera.com.
  • Henkel G; Arisan Therapeutics, San Diego, CA, USA. Electronic address: gregh@arisanthera.com.
Antiviral Res ; 193: 105125, 2021 09.
Article en En | MEDLINE | ID: mdl-34197863
Several arenaviruses, including Lassa and Lujo viruses in Africa and five New World arenavirus (NWA) species in the Americas, cause life-threatening viral hemorrhagic fevers. In the absence of licensed antiviral therapies, these viruses pose a significant public health risk. The envelope glycoprotein complex (GPC) mediates arenavirus entry through a pH-dependent fusion of the viral and host endosomal membranes. It thus is recognized as a viable target for small-molecule fusion inhibitors. Here, we report on the antiviral activity and pre-clinical development of the novel broad-spectrum arenavirus fusion inhibitors, ARN-75039 and ARN-75041. In Tacaribe virus (TCRV) pseudotyped and native virus assays, the ARN compounds were active in the low to sub-nanomolar range with selectivity indices exceeding 1000. Pharmacokinetic analysis of the orally administered compounds revealed an extended half-life in mice supporting once-daily dosing, and the compounds were well tolerated at the highest tested dose of 100 mg/kg. In a proof-of-concept prophylactic efficacy study, doses of 10 and 35 mg/kg of either compound dramatically improved survival outcome and potently inhibited TCRV replication in serum and various tissues. Additionally, in contrast to surviving mice that received ribavirin or placebo, animals treated with ARN-75039 or ARN-75041 were cured of TCRV infection. In a follow-up study with ARN-75039, impressive therapeutic efficacy was demonstrated under conditions where treatment was withheld until after the onset of disease. Taken together, the data strongly support the continued development of ARN-75039 as a candidate therapeutic for the treatment of severe arenaviral diseases.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antivirales / Arenavirus del Nuevo Mundo / Infecciones por Arenaviridae / Bibliotecas de Moléculas Pequeñas / Fusión de Membrana Tipo de estudio: Observational_studies / Prognostic_studies Límite: Animals Idioma: En Revista: Antiviral Res Año: 2021 Tipo del documento: Article Pais de publicación: Países Bajos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antivirales / Arenavirus del Nuevo Mundo / Infecciones por Arenaviridae / Bibliotecas de Moléculas Pequeñas / Fusión de Membrana Tipo de estudio: Observational_studies / Prognostic_studies Límite: Animals Idioma: En Revista: Antiviral Res Año: 2021 Tipo del documento: Article Pais de publicación: Países Bajos