Faculty Collaboration Database

Inhibition of Cytomegalovirus Replication with Extended-Half-Life Synthetic Ozonides. Antimicrob Agents Chemother 2019 Jan;63(1)

Date

10/31/2018

Pubmed ID

30373792

Pubmed Central ID

PMC6325236

DOI

10.1128/AAC.01735-18

Scopus ID

2-s2.0-85058920560 (requires institutional sign-in at Scopus site)   11 Citations

Abstract

Artesunate (AS), a semisynthetic artemisinin approved for malaria therapy, inhibits human cytomegalovirus (HCMV) replication in vitro, but therapeutic success in humans has been variable. We hypothesized that the short in vivo half-life of AS may contribute to the different treatment outcomes. We tested novel synthetic ozonides with longer half-lives against HCMV in vitro and mouse cytomegalovirus (MCMV) in vivo Screening of the activities of four ozonides against a pp28-luciferase-expressing HCMV Towne recombinant identified OZ418 to have the best selectivity; its effective concentration inhibiting viral growth by 50% (EC₅₀) was 9.8 ± 0.2 µM, and cytotoxicity in noninfected human fibroblasts (the concentration inhibiting cell growth by 50% [CC₅₀]) was 128.1 ± 8.0 µM. In plaque reduction assays, OZ418 inhibited HCMV TB40 in a concentration-dependent manner as well as a ganciclovir (GCV)-resistant HCMV isolate. The combination of OZ418 and GCV was synergistic in HCMV inhibition in vitro Virus inhibition by OZ418 occurred at an early stage and was dependent on the cell density at the time of infection. OZ418 treatment reversed HCMV-mediated cell cycle progression and correlated with the reduction of HCMV-induced expression of pRb, E2F1, and cyclin-dependent kinases 1, 2, 4, and 6. In an MCMV model, once-daily oral administration of OZ418 had significantly improved efficacy against MCMV compared to that of twice-daily oral AS. A parallel pharmacokinetic study with a single oral dose of OZ418 or AS showed a prolonged plasma half-life and higher unbound concentrations of OZ418 than unbound concentrations of AS. In summary, ozonides are proposed to be potential therapeutics, alone or in combination with GCV, for HCMV infection in humans.

Author List

Wang Y, Mukhopadhyay R, Roy S, Kapoor A, Su YP, Charman SA, Chen G, Wu J, Wang X, Vennerstrom JL, Arav-Boger R

Author

Ravit Boger MD Chief, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antiviral Agents
CDC2 Protein Kinase
Cell Line
Cytomegalovirus
Cytomegalovirus Infections
Drug Administration Schedule
Drug Evaluation, Preclinical
Drug Resistance, Viral
E2F1 Transcription Factor
Female
Fibroblasts
Ganciclovir
Gene Expression Regulation
Heterocyclic Compounds, 1-Ring
Host-Pathogen Interactions
Humans
Isoenzymes
Male
Mice
Mice, Inbred BALB C
Microbial Sensitivity Tests
Retinoblastoma Protein
Signal Transduction
Spiro Compounds
Virus Replication