Faculty Collaboration Database

The Synthesis and Anti-Cytomegalovirus Activity of Piperidine-4-Carboxamides. Viruses 2022 Jan 25;14(2)

Date

02/27/2022

Pubmed ID

35215828

Pubmed Central ID

PMC8876412

DOI

10.3390/v14020234

Scopus ID

2-s2.0-85123542102 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

Treatment options for human cytomegalovirus (CMV) remain limited and are associated with significant adverse effects and the selection of resistant CMV strains in transplant recipients and congenitally infected infants. Although most approved drugs target and inhibit the CMV DNA polymerase, additional agents with distinct mechanisms of action are needed for the treatment and prevention of CMV. In a large high throughput screen using our CMV-luciferase reporter Towne, we identified several unique inhibitors of CMV replication. Here, we synthesize and test in vitro 13 analogs of the original NCGC2955 hit (1). Analogs with no activity against the CMV-luciferase at 10 µM and 30 µM (2-6, 10-14) were removed from further analysis. Three analogs (7-9) inhibited CMV replication in infected human foreskin fibroblasts. The EC₅₀ of (1) was 1.7 ± 0.6 µM and 1.99 ± 0.15 µM, based on luciferase and plaque assay, respectively. Compounds 7, 8, and 9 showed similar activities: the EC₅₀ values of 7 were 0.21 ± 0.06 µM (luciferase) and 0.55 ± 0.06 (plaque), of 8: 0.28 ± 0.06 µM and 0.42 ± 0.07, and of 9: 0.30 ± 0.05 µM (luciferase) and 0.35 ± 0.07 (plaque). The CC₅₀ for 7, 8, and 9 in non-infected human foreskin fibroblasts was > 500µM, yielding a selectivity index of >1500. Compounds 1, 7, and 8 were also tested in CMV-infected primary human hepatocytes and showed a dose-response against CMV by luciferase activity and viral protein expression. None of the active compounds inhibited herpes simplex virus 1 or 2. Compounds 7 and 8 inhibited mouse CMV replication in vitro. Both inhibited CMV at late stages of replication; 7 reduced virus yield at all late time points, although not to the same degree as letermovir. Finally, the activity of analog 8 was additive with newly identified CMV inhibitors (MLS8969, NFU1827, MSL8554, and MSL8091) and with ganciclovir. Further structural activity development should provide promising anti-CMV agents for use in clinical studies.

Author List

Guo X, Ghosh AK, Keyes RF, Peterson F, Forman M, Meyers DJ, Arav-Boger R

Authors

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

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

Animals
Antiviral Agents
Cells, Cultured
Cytomegalovirus
Ganciclovir
Hepatocytes
Herpesvirus 1, Human
Herpesvirus 2, Human
Humans
Mice
Microbial Sensitivity Tests
Molecular Structure
Muromegalovirus
Structure-Activity Relationship
Viral Load
Virus Replication