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.
Highlights
Licensee MDPI, Basel, Switzerland.Infection with human cytomegalovirus (CMV), a member of the herpesvirus family, is common in humans
Their use is associated with considerable toxicities to the bone marrow
We recently reported oncompounds a successful completion of the largest largest high-throughput screen (HTS)
Summary
It the CMVCMV is the theis most common congenital infection worldwide [6,7,8].[6,7,8] It is the leading infectious cause of hearing loss and central nervous system damage in children. Iscause the most common infection worldwide is the leading infectious cause of hearing hearing losscongenital and central central nervous system damage inIt children. TheirTheir infectious cause of systemic hearing loss and central nervous system in children Their use is associated with considerable toxicities to the bone marrow (ganciclovir (GCV)). GCV, paving the way for the treatment of congenital phase clinical trial documented the prevention of hearing loss in congenitally infected children treated with with intravenous. The overall problems of toxicity, resistance, oral-bioavailability, and high-cost cost drug discovery.
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