title: Identification of inhibitors that block vaccinia virus infection by targeting the DNA synthesis processivity factor D4.
abstract: Smallpox was globally eradicated 30 years ago by vaccination. The recent threat of bioterrorism demands the development of improved vaccines and novel therapeutics to effectively preclude a reemergence of smallpox. One new therapeutic target is the vaccinia poxvirus processivity complex, comprising D4 and A20 proteins that enable the viral E9 DNA polymerase to synthesize extended strands. Five compounds identified from an AlphaScreen assay designed to disrupt A20:D4 binding were shown to be effective in: (i) blocking vaccinia processive DNA synthesis in vitro, (ii) preventing cellular infection with minimal cytotoxicity, and (iii) binding to D4, as evidenced by ThermoFluor. The EC(50) values for inhibition of viral infectivity ranged from 9.6 to 23 μM with corresponding selectivity indices (cytotoxicity CC(50)/viral infectivity EC(50)) of 3.9 to 17.8. The five compounds are thus potential therapeutics capable of halting smallpox DNA synthesis and infectivity through disruptive action against a component of the vaccinia processivity complex.
authors: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
authors: Manunya
authors: M
authors: Nuth
authors: Lijuan
authors: L
authors: Huang
authors: Yih Ling
authors: YL
authors: Saw
authors: Norbert
authors: N
authors: Schormann
authors: Debasish
authors: D
authors: Chattopadhyay
authors: Robert P
authors: RP
authors: Ricciardi
mesh_terms: D000627:Aminophenols / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D002522:Chlorocebus aethiops; D004279:DNA, Viral / Q000096:biosynthesis*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding; D012899:Smallpox / Q000378:metabolism / Q000517:prevention & control*; D013329:Structure-Activity Relationship; D014616:Vaccinia virus / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C559861:10-(cyclohexylamino)-12-((2-hydroxyethyl)amino)-15-oxa-14-azatetracyclohexadeca-1(16),2,4,6,9,11,13-heptaen-8-one; C559862:4-(((2-(benzyloxy)phenyl)methyl)amino)phenol; D000627:Aminophenols; D000998:Antiviral Agents; D004279:DNA, Viral; D006576:Heterocyclic Compounds, 4 or More Rings; D046912:Multiprotein Complexes; D014764:Viral Proteins