200 Potent inhibition of HIV replication by RNA-binding peptide mimetics with unprecedented specificity

Abstract

RNA provides an inviting target for pharmaceutical intervention in both infectious and chronic diseases, but it has so far been impossible to identify drug-like molecules with sufficient potency to lead to the successful clinical applications. We have developed a new class of structurally constrained cyclic peptides to target the interaction between the human immunodeficiency virus (HIV-1) transactivator protein Tat and its response element TAR (1,2), which plays an essential role in viral replication. Many previous attempts to inhibit this interaction have failed to yield molecules with sufficient potency and specificity to warrant pharmaceutical development. The peptidic mimics of Tat that are pM inhibitors of the Tat-TAR interaction and discriminate > 1000 fold between closely related RNAs. They are potent inhibitors of viral replication (tens of nM) with no cytotoxicity and efficient cell penetration which specifically inhibit TAR-dependent reverse transcription as well as activation of transcription, and repress replication of a wide variety of viral strains representing all the major HIV clades in primary human lymphocytes (3). The potency and selectivity observed for this family of peptides is unprecedented among Tat inhibitors and suggest that peptides of this class may be more widely useful for the pharmacological inhibition of other protein–RNA interactions.