Target‐Directed Azide‐Alkyne Cycloaddition for Assembling HIV‐1 TAR RNA Binding Ligands

Abstract

The highly conserved HIV‐1 transactivation response element (TAR) binds to the trans‐activator protein Tat and facilitates the viral replication in its latent state. The inhibition of Tat–TAR interactions by selectively targeting TAR RNA has been used as a strategy to develop potent anti‐viral agents. Therefore, HIV‐1 TAR RNA represents a paradigmatic system for therapeutic intervention. Herein, we have employed biotin tagged TAR RNA to assemble its own ligands from a pool of reactive azide‐alkyne building blocks. In order to identify binding sites and selectivity of ligands the in situ cycloaddition has been further performed using control nucleotide (TAR DNA and TAR RNA w/b) templates. The hit triazole linked thiazole peptidomimetic products were isolated from the biotin tagged target templates using streptavidin beads. The major triazole lead generated by the TAR RNA presumably binds in the bulge region, shows specificity for TAR RNA over TAR DNA and inhibits Tat‐TAR interactions.