ARTICLE | Distillery Therapeutics

Therapeutics: Caspase-3 (CASP3; CPP32); cyclin dependent kinase (CDK)

September 29, 2016 7:00 AM UTC

Cell culture studies suggest the pan-caspase inhibitor emricasan, the generic antihelminthic niclosamide or CDK inhibitors could help treat Zika. In a Zika virus-infected human glioblastoma cell line, screening of 6,000 approved drugs, tool compounds and other small molecules identified emricasan, niclosamide and a CDK inhibitor tool compound that inhibited virus-induced cell death with IC50 values of 0.87 μM, 1.96 μM and 10.9 μM, respectively, and virus-induced caspase-3 (CASP3; CPP32) activation with IC50 values of 0.62 μM, 2.06 μM and 9.2 μM. In the Zika virus-infected cell line, nine structually distinct CDK inhibitors - seliciclib, dinaciclib and alvocidib flavopiridol and six tool compounds - decreased viral titers with IC50 values of 24-355 nM. In cultured human induced pluripotent stem (iPS) cell-derived neural progenitor cells or astrocytes infected with Zika virus, emricasan decreased virus-induced CASP3 levels, and niclosamide or the CDK inhibitor decreased infectivity compared with vehicle. Next steps include testing the compounds in animal models of Zika.

Conatus Pharmaceuticals Inc. has emricasan (IDN-6556; PF-03491390; PF-3491390) in Phase II testing for cirrhosis, non-alcoholic steatohepatitis (NASH) and other liver diseases and in Phase I/II testing for diabetes...