title: Broad-spectrum non-nucleoside inhibitors of human herpesviruses.
abstract: Herpesvirus infections cause considerable morbidity and mortality through lifelong recurrent cycles of lytic and latent infection in several tissues, including the human nervous system. Acyclovir (ACV) and its prodrug, the current antivirals of choice for herpes simplex virus (HSV) and, to some extent, varicella zoster virus (VZV) infections are nucleoside analogues that inhibit viral DNA replication. Rising viral resistance and the need for more effective second-line drugs have motivated searches for additional antiviral agents, particularly non-nucleoside based agents. We evaluated the antiviral activity of five compounds with predicted lysosomotropic activity using conventional and human induced pluripotent stem cell-derived neuronal (iPSC-neurons) cultures. Their potency and toxicity were compared with ACV and the lysosomotropic agents chloroquine and bafilomycin A1. Out of five compounds tested, micromolar concentrations of 30N12, 16F19, and 4F17 showed antiviral activity comparable to ACV (50μM) during lytic herpes simplex virus type 1 (HSV-1) infections, reduced viral DNA copy number, and reduced selected HSV-1 protein levels. These compounds also inhibited the reactivation of 'quiescent' HSV-1 infection established in iPSC-neurons, but did not inhibit viral entry into host cells. The same compounds had greater potency than ACV against lytic VZV infection; they also inhibited replication of human cytomegalovirus. The anti-herpetic effects of these non-nucleoside agents merit further evaluation in vivo.
authors.affiliation: Department of Psychiatry, WPIC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Lora
authors.initials: L
authors.lastname: McClain
authors.affiliation: Department of Psychiatry, WPIC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhi
authors.affiliation: Department of Psychiatry, WPIC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Hoyee
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Department of Psychiatry, WPIC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Ayantika
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Piazza
authors.affiliation: Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Yee
authors.affiliation: Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Jadranka
authors.initials: J
authors.lastname: Milosevic
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Bloom
authors.affiliation: Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Ravit
authors.initials: R
authors.lastname: Arav-Boger
authors.affiliation: Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Molecular Genetics & Biochemistry, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Kinchington
authors.affiliation: Stanley Division of Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Yolken
authors.affiliation: Department of Psychiatry, WPIC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Vishwajit
authors.initials: V
authors.lastname: Nimgaonkar
authors.affiliation: Department of Psychiatry, WPIC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: daiutol@upmc.edu.
authors.forename: Leonardo
authors.initials: L
authors.lastname: D'Aiuto
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000302:isolation & purification* / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006564:Herpesviridae / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009474:Neurons / Q000821:virology
chemical_list: D000998:Antiviral Agents
keywords: Antiviral; HSV; Herpes simplex virus type 1; Human cytomegalovirus; Induced pluripotent stem cells; Varicella zoster virus