Targeting RNA remains to be a formidable challenge. To develop compounds as possible RNA therapeutics, our laboratories are focused on molecular recognition of the three dimensional architecture of conserved RNAs present in HIV-1 Rev response element (RRE). Using a library of branched peptides composed of unnatural amino acids—some with boronic acids, potent and selective binders of RRE RNA were discovered. Binding of Rev to RRE is essential for the transport of full length RNA transcripts to the cytoplasm, which is a key step in the viral replication process. Hence, inhibitors of this interaction have the potential as therapeutics. We will discuss the synthesis of the library, high throughput screen, and biophysical characterization of hit peptides. We discovered inhibitors in the nanomolar range against RRE RNA: peptide branching and formation of reversible covalent bonds with boronic acids and 2’-hydroxyl group of RNA are key intermolecular interactions. SHAPE analysis reveal binding sites with full length RNA and in vitro studies suggest inhibition of viral replication in a Rev-RRE RNA interaction dependent manner.

Targeting RNA with branched peptide boronic acids: Unnatural amino acids, molecular recognition, and in vitro activity against HIV-1 RRE RNA

253rd National Meeting (2017)

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