Premium
Phenotypic Prioritization of Diphyllin Derivatives That Block Filoviral Cell Entry by Vacuolar (H + )‐ATPase Inhibition
Author(s) -
Lindstrom Aaron,
Anantpadma Manu,
Baker Logan,
Raghavendra N. M.,
Davey Robert,
Davisson Vincent Jo
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800587
Subject(s) - endosome , viral entry , cytotoxicity , potency , microbiology and biotechnology , cytosol , entry inhibitor , cell culture , biology , ebola virus , atpase , viral replication , chemistry , biochemistry , virus , cell , in vitro , enzyme , virology , genetics
Abstract Many viruses use endosomal pathways to gain entry into cells and propagate infection. Sensing of endosomal acidification is a trigger for the release of many virus cores into the cell cytosol. Previous efforts with inhibitors of vacuolar ATPase have been shown to block endosomal acidification and affect viral entry, albeit with limited potential for therapeutic selectivity. In this study, four novel series of derivatives of the vacuolar ATPase inhibitor diphyllin were synthesized to assess their potential for enhancing potency and anti‐filoviral activity over cytotoxicity. Derivatives that suitably blocked cellular entry of Ebola pseudotyped virus were further evaluated as inhibitors of endosomal acidification and isolated human vacuolar ATPase activity. Several compounds with significant increases in potency over diphyllin in these assays also separated from cytotoxic doses in human cell models by >100‐fold. Finally, three derivatives were shown to be inhibitors of replication‐competent Ebola viral entry into primary macrophages with similar potencies and enhanced selectivity toward antiviral activity.