Phenotypical Screening of an MMV Open Box Library and Identification of Compounds with Antiviral Activity against St. Louis Encephalitis Virus

Author(s)

Sotorilli, Giuliana Eboli ; Gravina, Humberto Doriguetto ; de Carvalho, Ana Carolina ; Shimizu, Jacqueline Farinha ; Fontoura, Marina Alves ; Melo-Hanchuk, Talita Diniz ; Cordeiro, Artur Torres ; Marques, Rafael Elias

• Document type: Journal article
• Source: Viruses-Basel; v. 15, n. 12, p. 16-pg., 2023-12-01.

Abstract

St. Louis encephalitis virus (SLEV) is a neglected mosquito-borne Flavivirus that may cause severe neurological disease in humans and other animals. There are no specific treatments against SLEV infection or disease approved for human use, and drug repurposing may represent an opportunity to accelerate the development of treatments against SLEV. Here we present a scalable, medium-throughput phenotypic cell culture-based screening assay on Vero CCL81 cells to identify bioactive compounds that could be repurposed against SLEV infection. We screened eighty compounds from the Medicines for Malaria Venture (MMV) COVID Box library to identify nine (11%) compounds that protected cell cultures from SLEV-induced cytopathic effects, with low- to mid-micromolar potencies. We validated six hit compounds using viral plaque-forming assays to find that the compounds ABT-239, Amiodarone, Fluphenazine, Posaconazole, Triparanol, and Vidofludimus presented varied levels of antiviral activity and selectivity depending on the mammalian cell type used for testing. Importantly, we identified and validated the antiviral activity of the anti-flavivirus nucleoside analog 7DMA against SLEV. Triparanol and Fluphenazine reduced infectious viral loads in both Vero CCL81 and HBEC-5i cell cultures and, similar to the other validated compounds, are likely to exert antiviral activity through a molecular target in the host. (AU)

• FAPESP's process: 18/10990-1 - Characterization and therapeutic potential of chemokine action in sepsis and Flavivirus-induced encephalitis
• Grantee: Rafael Elias Marques Pereira Silva
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/05519-0 - Understanding the role of neutrophil recruitment and activation in arboviral diseases
• Grantee: Rafael Elias Marques Pereira Silva
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/02993-0 - Development of the first experimental model of Ilheus Virus (ILHV) infection in mice and design of therapeutic strategies
• Grantee: Ana Carolina de Carvalho
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)