Design, Synthesis, and Biological Evaluation of Antiviral Agents Targeting Flavivirus Envelope Proteins

• DOI: 10.1021/jm800412d
• Publication Date: 2008-07-09T09:00:29Z
• Authors: Ze Li; Mansoora Khaliq; Zhigang Zhou; Carol Beth Post; Richard J. Kuhn; Mark Cushman
• Keywords: Models, Molecular; Structure-Activity Relationship; 0303 health sciences; 03 medical and health sciences; Binding Sites; Molecular Structure; Drug Design; Flavivirus; Gene Products, env; Antiviral Agents; 3. Good health

Flavivirus envelope proteins (E proteins) have been shown to play a pivotal role in virus assembly, morphogenesis, and infection of host cells. Inhibition of flavivirus infection of a host cell by means of a small molecule envelope protein antagonist is an attractive strategy for the development of antiviral agents. Virtual screening of the NCI chemical database using the dengue virus envelope protein structure revealed several hypothetical hit compounds. Bioassay results identified a class of thiazole compounds with antiviral potency in cell-based assays. Modification of these lead compounds led to a series of analogues with improved antiviral activity and decreased cytotoxicity. The most active compounds 11 and 36 were effective in the low micromolar concentration range in a cellular assay system.