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Small-molecule screening using a whole-cell viral replication reporter gene assay identifies 2-{[2-(benzoylamino)benzoyl]amino}-benzoic acid as a novel antiadenoviral compound.

Abstract
Adenovirus infections are widespread in society and are occasionally associated with severe, but rarely with life-threatening, disease in otherwise healthy individuals. In contrast, adenovirus infections present a real threat to immunocompromised individuals and can result in disseminated and fatal disease. The number of patients undergoing immunosuppressive therapy for solid organ or hematopoietic stem cell transplantation is steadily increasing, as is the number of AIDS patients, and this makes the problem of adenovirus infections even more urgent to solve. There is no formally approved treatment of adenovirus infections today, and existing antiviral agents evaluated for their antiadenoviral effect give inconsistent results. We have developed a whole cell-based assay for high-throughput screening of potential antiadenoviral compounds. The assay is unique in that it is based on a replication-competent adenovirus type 11p green fluorescent protein (GFP)-expressing vector (RCAd11pGFP). This allows measurement of fluorescence changes as a direct result of RCAd11pGFP genome expression. Using this assay, we have screened 9,800 commercially available small organic compounds. Initially, we observed approximately 400 compounds that inhibited adenovirus expression in vitro by > or = 80%, but only 24 were later confirmed as dose-dependent inhibitors of adenovirus. One compound in particular, 2-{[2-(benzoylamino)benzoyl]amino}-benzoic acid, turned out to be a potent inhibitor of adenovirus replication.
AuthorsEmma K Andersson, Mårten Strand, Karin Edlund, Kristina Lindman, Per-Anders Enquist, Sara Spjut, Annika Allard, Mikael Elofsson, Ya-Fang Mei, Göran Wadell
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 54 Issue 9 Pg. 3871-7 (Sep 2010) ISSN: 1098-6596 [Electronic] United States
PMID20585112 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antiviral Agents
  • Benzoic Acid
Topics
  • Adenoviridae (drug effects, genetics)
  • Antiviral Agents (chemistry, pharmacology)
  • Benzoic Acid (chemistry, pharmacology)
  • Cell Line, Tumor
  • Flow Cytometry
  • Genes, Reporter (genetics)
  • Humans
  • Polymerase Chain Reaction
  • Virus Replication (drug effects, genetics)

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