Optimization and determination of the absolute configuration of a series of potent inhibitors of human papillomavirus type-11 E1-E2 protein-protein interaction: a combined medicinal chemistry, NMR and computational chemistry approach.

We have previously reported the discovery and initial SAR optimization of the first series of inhibitors of the human papillomavirus type-11 (HPV11) E1-E2 protein-protein interaction. These inhibitors featured an indandione system spiro-fused onto an all syn substituted tetrahydrofuran ring. In this paper, we report new SAR efforts which have led to the identification of the first low nanomolar inhibitor of the HPV11 E1-E2 protein-protein interaction. In addition, we report a combined NMR and computational chemistry approach which allowed the successful determination of the absolute stereochemistry of the active species originating from the initial racemic lead.

Improved replicon cellular activity of non-nucleoside allosteric inhibitors of HCV NS5B polymerase: from benzimidazole to indole scaffolds.

Benzimidazole-based allosteric inhibitors of the hepatitis C virus (HCV) NS5B polymerase were diversified to a variety of topologically related scaffolds. Replacement of the polar benzimidazole core by lipophilic indoles led to inhibitors with improved potency in the cell-based subgenomic HCV replicon system. Transposing the indole scaffold into a previously described series of benzimidazole-tryptophan amides generated the most potent inhibitors of HCV RNA replication in cell culture reported to date in this series (EC(50) approximately 50 nM).

Discovery of the first series of inhibitors of human papillomavirus type 11: inhibition of the assembly of the E1-E2-Origin DNA complex.

We have discovered a series of inhibitors of the assembly of the HPV11 E1-E2-origin DNA complex, which incorporate an indandione fused to a substituted tetrahydrofuran.