Open AccessValidation and Characterization of Five Distinct Novel Inhibitors of Human Cytomegalovirus
Author(s) -
Arun Kapoor,
Ayan Ghosh,
Michael Forman,
Xin Hu,
Wenjuan Ye,
Noel Southall,
Juan Marugán,
Robert F. Keyes,
Brian C. Smith,
David J. Meyers,
Marc Ferrer,
Ravit AravBoger
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.9b01501
Subject(s) - human cytomegalovirus , ganciclovir , herpes simplex virus , cytomegalovirus , chemistry , herpesviridae , virology , virus , recombinant dna , population , high throughput screening , antiviral drug , biological activity , in vitro , biology , gene , viral disease , biochemistry , medicine , environmental health
The critical consequences of human cytomegalovirus (HCMV) infection in the transplant population and in congenitally infected infants, the limited treatment options for HCMV, and the rise of resistant mutants toward existing therapies has fueled the search for new anti-HCMV agents. A pp28-luciferase recombinant HCMV was used as a reporter system for high-throughput screening of HCMV inhibitors. Approximately 400 000 compounds from existing libraries were screened. Subsequent validation assays using resynthesized compounds, several virus strains, and detailed virology assays resulted in the identification of five structurally unique and selective HCMV inhibitors, active at sub to low micromolar concentrations. Further characterization revealed that each compound inhibited a specific stage of HCMV replication. One compound was also active against herpes simplex virus (HSV1 and HSV2), and another compound was active against Epstein-Barr virus (EBV). Drug combination studies revealed that all five compounds were additive with ganciclovir or letermovir. Future studies will focus on optimization of these new anti-HCMV compounds along with mechanistic studies.