Design, Synthesis and Evaluation of RNA-binding [2.2.1] Bicyclic Scaffolds: Application to HIV-1 Tat/TAR Inhibition

In this paper, a [2.2.1] bicyclic core is applied as a peptidomimetic scaffold capable of reproducing the structural relationship between the critical residues of the Tat protein, in an effort to create small molecules capable of binding to TAR RNA and inhibiting the Tat/TAR interaction. A systematic twenty-member panel mimicking an Arginine-Aspartic acid (R-D) moiety was synthesized and the ability of the individual members to inhibit the Tat/TAR interaction was evaluated. A gel-shift mobility assay was used to establish that several bicyclic agents inhibited the RNA-protein interaction with a micromolar level of activity.