title: A novel target and approach for identifying antivirals against molluscum contagiosum virus.
abstract: The dermatological disease molluscum contagiosum (MC) presents as lesions restricted solely to the skin. The poxvirus molluscum contagiosum virus (MCV) is responsible for this skin disease that is easily transmitted through casual contact among all populations, with greater frequency in children and immunosuppressed individuals. In addition, sexual transmission of MCV in adolescents and adults is a health concern. Although the skin lesions ultimately resolve in immunocompetent individuals, they can persist for extended periods, be painful, and result in scarring. Treatment is problematic, and there is no drug that specifically targets MCV. The inability of MCV to propagate in cell culture has impeded drug development. To overcome these barriers, we integrated three new developments. First, we identified a new MCV drug target (mD4) that is essential for processive DNA synthesis in vitro. Second, we discovered a small chemical compound that binds to mD4 and prevents DNA synthesis in vitro. Third, and most significant, we engineered a hybrid vaccinia virus (mD4-VV) in which the natural vaccinia D4 (vD4) gene is replaced by the mD4 target gene. This hybrid virus is dependent on mD4 for viral growth in culture and is inhibited by the small compound. This target system provides, for the first time, a platform and approach for the discovery and evaluation of new therapeutics that can be used to treat MC.
authors.affiliation: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Hancheng
authors.initials: H
authors.lastname: Guan
authors.affiliation: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Manunya
authors.initials: M
authors.lastname: Nuth
authors.affiliation: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Zhukovskaya
authors.affiliation: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Yih Ling
authors.initials: YL
authors.lastname: Saw
authors.affiliation: Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Bell
authors.affiliation: Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Stuart N
authors.initials: SN
authors.lastname: Isaacs
authors.affiliation: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA Abramson Cancer Center, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA ricciard@upenn.edu.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Ricciardi
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D001681:Biological Assay; D002460:Cell Line; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D004279:DNA, Viral; D004259:DNA-Directed DNA Polymerase / Q000235:genetics* / Q000378:metabolism; D055808:Drug Discovery; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology / Q000821:virology; D015870:Gene Expression; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000821:virology; D058990:Molecular Targeted Therapy; D008977:Molluscum contagiosum virus / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D011817:Rabbits; D016865:Reassortant Viruses / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D014616:Vaccinia virus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D014764:Viral Proteins; D004259:DNA-Directed DNA Polymerase