Inhibitors of nucleotidyltransferase superfamily enzymes suppress herpes simplex virus replication

• Published in: Antimicrobial agents and chemotherapy 2014-12, Vol.58 (12), p.7451-7461
• Main Authors: Tavis, John E, Wang, Hong, Tollefson, Ann E, Ying, Baoling, Korom, Maria, Cheng, Xiaohong, Cao, Feng, Davis, Katie L, Wold, William S M, Morrison, Lynda A
• Format: Article
• Language: English
• Subjects: Acyclovir - pharmacology; Animals; Antiviral Agents; Antiviral Agents - pharmacology; Cercopithecus aethiops; Cytomegalovirus - drug effects; Cytomegalovirus - enzymology; Cytomegalovirus - growth & development; DNA Replication - drug effects; DNA, Viral - antagonists & inhibitors; DNA, Viral - genetics; DNA, Viral - metabolism; Dose-Response Relationship, Drug; Drug Resistance, Viral - drug effects; Enzyme Inhibitors; Enzyme Inhibitors - pharmacology; Fibroblasts - drug effects; Fibroblasts - virology; Herpes simplex virus 1; Herpes simplex virus 2; Herpesvirus; Herpesvirus 1, Human; Herpesvirus 1, Human - drug effects; Herpesvirus 1, Human - enzymology; Herpesvirus 1, Human - growth & development; Herpesvirus 2, Human; Herpesvirus 2, Human - drug effects; Herpesvirus 2, Human - enzymology; Herpesvirus 2, Human - growth & development; Human cytomegalovirus; Humans; Nucleotidyltransferases; Nucleotidyltransferases - antagonists & inhibitors; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; Primary Cell Culture; Small Molecule Libraries; Small Molecule Libraries - pharmacology; Vero Cells; Viral Proteins; Viral Proteins - antagonists & inhibitors; Viral Proteins - genetics; Viral Proteins - metabolism; Virus Replication - drug effects
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.03875-14

Herpesviruses are large double-stranded DNA viruses that cause serious human diseases. Herpesvirus DNA replication depends on multiple processes typically catalyzed by nucleotidyltransferase superfamily (NTS) enzymes. Therefore, we investigated whether inhibitors of NTS enzymes would suppress replication of herpes simplex virus 1 (HSV-1) and HSV-2. Eight of 42 NTS inhibitors suppressed HSV-1 and/or HSV-2 replication by >10-fold at 5 μM, with suppression at 50 μM reaching ∼1 million-fold. Five compounds in two chemical families inhibited HSV replication in Vero and human foreskin fibroblast cells as well as the approved drug acyclovir did. The compounds had 50% effective concentration values as low as 0.22 μM with negligible cytotoxicity in the assays employed. The inhibitors suppressed accumulation of viral genomes and infectious particles and blocked events in the viral replication cycle before and during viral DNA replication. Acyclovir-resistant mutants of HSV-1 and HSV-2 remained highly sensitive to the NTS inhibitors. Five of six NTS inhibitors of the HSVs also blocked replication of another herpesvirus pathogen, human cytomegalovirus. Therefore, NTS enzyme inhibitors are promising candidates for new herpesvirus treatments that may have broad efficacy against members of the herpesvirus family.