BioCentury
ARTICLE | Distillery Therapeutics

Therapeutics: Calmodulin; CDC-like kinase 1 (CLK-1); vascular endothelial growth factor receptor 3 (FLT4; VEGFR-3); K(lysine) acetyltransferase 5 (KAT5); acetyl

June 9, 2016 7:00 AM UTC

Cell culture and mouse studies identified inhibitors of calmodulin, CLK-1, FLT4, KAT5 and other host factors that could help treat Chikungunya viral infection. Screening of an siRNA library targeting about 17,000 genes and 6,000 open reading frames (ORFs) in a Chikungunya virus-infected human cell line identified 156 host factors that promoted viral infection, and analysis of chemical databases identified 52 small molecule inhibitors of 14 of those host factors. In a human cell line infected with Chikungunya virus, compounds inhibiting five of the 14 factors - calmodulin signaling, CLK-1, fatty acid synthesis, FLT4 and KAT5 - decreased viral replication, and bafilomycin - an inhibitor of a sixth factor, vacuolar ATPases - decreased viral entry compared with vehicle, without causing observable cytotoxicity. In a mouse model of Chikungunya viral infection, the calmodulin inhibitor pimozide, the FLT4 inhibitor tivozanib and an ACAC inhibitor tool compound that blocks fatty acid synthesis decreased viral loads and increased survival compared with vehicle. Also in the model, pimozide plus the ACAC inhibitor decreased viral replication and joint swelling compared with either compound alone. Next steps include determining which of the identified compounds is most effective and optimizing it for clinical development.

The generic pimozide is marketed to treat schizophrenia, Tourette's syndrome and chronic psychosis. ...