title: The Microtubule Inhibitor Podofilox Inhibits an Early Entry Step of Human Cytomegalovirus.
abstract: Human cytomegalovirus is a ubiquitous β-herpesvirus that infects many different cell types through an initial binding to cell surface receptors followed by a fusion event at the cell membrane or endocytic vesicle. A recent high-throughput screen to identify compounds that block a step prior to viral gene expression identified podofilox as a potent and nontoxic inhibitor. Time-of-addition studies in combination with quantitative-PCR analysis demonstrated that podofilox limits an early step of virus entry at the cell surface. Podofilox was also able to drastically reduce infection by herpes simplex 1, an α-herpesvirus with a very similar entry process to CMV. Podofilox caused a reduced maximal plateau inhibition of infection by viruses with single step binding processes prior to fusion-like Newcastle disease virus, Sendai virus, and influenza A virus or viruses that enter via endocytosis like vesicular stomatitis virus and a clinical-like strain of CMV. These results indicate that microtubules appear to be participating in the post-binding step of virus entry including the pre- and post-penetration events. Modulation of the plasma membrane is required to promote virus entry for herpesviruses, and that podofilox, unlike colchicine or nocodazole, is able to preferentially target microtubule networks at the plasma membrane.
authors: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. tobias.cohen@icahn.mssm.edu.
authors: Tobias
authors: T
authors: Cohen
authors: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. toni.schwarz@mssm.edu.
authors: Toni M
authors: TM
authors: Schwarz
authors: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. frederic.vigant@mssm.edu.
authors: Frederic
authors: F
authors: Vigant
authors: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Thomas.gardner@icahn.mssm.edu.
authors: Thomas J
authors: TJ
authors: Gardner
authors: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. rosmel.hernandez@icahn.mssm.edu.
authors: Rosmel E
authors: RE
authors: Hernandez
authors: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. benhur.lee@mssm.edu.
authors: Benhur
authors: B
authors: Lee
authors: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. domenico.tortorella@mssm.edu.
authors: Domenico
authors: D
authors: Tortorella
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects / Q000502:physiology*; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000502:physiology; D006801:Humans; D011034:Podophyllotoxin / Q000494:pharmacology*; D012328:RNA Viruses / Q000187:drug effects / Q000502:physiology; D050257:Tubulin Modulators / Q000494:pharmacology*; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D050257:Tubulin Modulators; D011034:Podophyllotoxin
keywords: colchicine; cytomegalovirus; microtubules; nocodazole; podofilox; virus entry