Validation and Characterization of Five Distinct Novel Inhibitors of Human Cytomegalovirus. J Med Chem 2020 Apr 23;63(8):3896-3907
Date
03/20/2020Pubmed ID
32191456Pubmed Central ID
PMC7386824DOI
10.1021/acs.jmedchem.9b01501Scopus ID
2-s2.0-85084027851 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
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.
Author List
Kapoor A, Ghosh AK, Forman M, Hu X, Ye W, Southall N, Marugan J, Keyes RF, Smith BC, Meyers DJ, Ferrer M, Arav-Boger RAuthors
Ravit Boger MD Chief, Professor in the Pediatrics department at Medical College of WisconsinAyan K. Ghosh PhD Research Scientist I in the Pediatrics department at Medical College of Wisconsin
Robert Keyes PhD Research Scientist II in the Biochemistry department at Medical College of Wisconsin
Brian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAntiviral Agents
Cells, Cultured
Cytomegalovirus
Cytomegalovirus Infections
Dose-Response Relationship, Drug
Drug Discovery
Fibroblasts
Humans
Male
Mice
