title: Design of potent poxvirus inhibitors of the heterodimeric processivity factor required for viral replication.
abstract: Smallpox constitutes a major bioterrorism threat, which underscores the need to develop antiviral drugs for rapid response in the event of an attack. Viral processivity factors are attractive drug targets in being both specific and essential for their cognate DNA polymerases to synthesize extended strands of DNA. An in silico model of the vacinnia virus processivity factor, comprised of the A20 and D4 heterocomplex, was constructed and used for lead optimization of an indole-based scaffold identified earlier from a high-throughput screening. On the basis of this model, a new class of potent antivirals against vaccinia virus was designed and synthesized, of which two (24a and 24b) exhibited superior improvement over the parent scaffold (IC50 = 42 and 46 vs 82000 nM, respectively). The ability of 24a to suppress vaccinia DNA synthesis is supported by the inhibition of late viral gene expression, as well as by the diminished incorporation of bromodeoxyuridine into viral replication factories.
authors.affiliation: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, PA 19104, USA.
authors.forename: Manunya
authors.initials: M
authors.lastname: Nuth
authors.forename: Hancheng
authors.initials: H
authors.lastname: Guan
authors.forename: Natalia
authors.initials: N
authors.lastname: Zhukovskaya
authors.forename: Yih Ling
authors.initials: YL
authors.lastname: Saw
authors.forename: Robert P
authors.initials: RP
authors.lastname: Ricciardi
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004279:DNA, Viral / Q000096:biosynthesis; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D013329:Structure-Activity Relationship; D014615:Vaccinia / Q000517:prevention & control; D014616:Vaccinia virus / Q000187:drug effects*; D014764:Viral Proteins / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
chemical_list: C581988:2-(3-((3,5-dichlorophenyl)thio)-6-methyl-1H-indol-2-yl)acetamide; C581987:3-(3-((3,5-dichlorophenyl)thio)-6-methyl-1H-indol-2-yl)propanamide; D000998:Antiviral Agents; D004279:DNA, Viral; D007211:Indoles; D014764:Viral Proteins