Abstract: Many important biological pathways, from the interferon antiviral response to the generation of microRNA regulators of translation, involve duplex RNA. The Beal group has investigated the use of helix-threading peptides as a general recognition motif for duplex RNA. Here we describe solid phase synthesis approaches to peptides with an acridine or quinoline chromophore introduced into the backbone. These compounds bind duplex RNA by threading intercalation with peptide appendages on the chromophore localized in the different helix grooves. In vitro evolution of RNA binding sites and structure-activity relationship studies revealed preferred RNA motifs that bind selectively to helix-threading peptides. Data will be presented regarding their binding affinity and selectivity for various RNA targets, including to a site found in a human pre-miRNA.