Two thiosemicarbazones derived from 1-indanone as potent non-nucleoside inhibitors of bovine viral diarrhea virus of different genotypes and biotypes

• Published in: Virology (New York, N.Y.) N.Y.), 2024-10, Vol.598, p.110189, Article 110189
• Main Authors: Fabiani, Matías, Castro, Eliana F., Battini, Leandro, Rosas, Rocío A., Gärtner, Benjamin, Bollini, Mariela, Cavallaro, Lucía V.
• Format: Article
• Language: English
• Subjects: Animals; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Bovine viral diarrhea virus; Cattle; Cell Line; Diarrhea Virus 1, Bovine Viral - drug effects; Diarrhea Virus 1, Bovine Viral - genetics; Diarrhea Virus 2, Bovine Viral - drug effects; Diarrhea Virus 2, Bovine Viral - genetics; Diarrhea Viruses, Bovine Viral - drug effects; Diarrhea Viruses, Bovine Viral - genetics; Drug resistance; Drug Resistance, Viral - genetics; Genotype; Indans - chemistry; Indans - pharmacology; Molecular dynamics; Mutation; Non-nucleoside inhibitors; RNA, Viral - genetics; RNA-Dependent RNA polymerase; RNA-Dependent RNA Polymerase - antagonists & inhibitors; RNA-Dependent RNA Polymerase - genetics; RNA-Dependent RNA Polymerase - metabolism; Thiosemicarbazones; Thiosemicarbazones - chemistry; Thiosemicarbazones - pharmacology; Virus Replication - drug effects
• ISSN: 0042-6822; 1096-0341; 1096-0341
• DOI: 10.1016/j.virol.2024.110189

Bovine viral diarrhea virus (BVDV) is a widespread pathogen of cattle and other mammals that causes major economic losses in the livestock industry. N4-TSC and 6NO2-TSC are two thiosemicarbazones derived from 1-indanone that exhibit anti-BVDV activity in vitro. These compounds selectively inhibit BVDV and are effective against both cytopathic and non-cytopathic BVDV-1 and BVDV-2 strains. We confirmed that N4-TSC acts at the onset of viral RNA synthesis, as previously reported for 6NO2-TSC. Moreover, resistance selection and characterization showed that N4-TSCR mutants were highly resistant to N4-TSC but remained susceptible to 6NO2-TSC. In contrast, 6NO2-TSCR mutants were resistant to both compounds. Additionally, mutations N264D and A392E were found in the viral RNA-dependent RNA polymerase (RdRp) of N4-TSCR mutants, whereas I261 M was found in 6NO2-TSCR mutants. These mutations lay in a hydrophobic pocket within the fingertips region of BVDV RdRp that has been described as a “hot spot” for BVDV non-nucleoside inhibitors. •N4-TSC and 6NO2-TSC inhibit both cytopathic and non-cytopathic BVDV-1 and BVDV-2.•Selected resistant BVDV carry mutations in the fingertips region of the viral RNA-polymerase.•Mutations N264D and A392E were associated with resistance to N4-TSC.•Mutation I261 M was found associated with resistance to 6NO2-TSC.