Targeting folded RNA: A branched peptide boronic acid that binds to a large surface area of HIV-1 RRE RNA

摘要

On-bead high throughput screening of a medium sized (1000–2000 Da) branched peptide boronic acid (BPBA) library consisting of 46,656 unique sequences against HIV-1 RRE RNA generated peptides with binding affinities in the low micromolar range. In particular, >BPBA1 had a Kd of 1.4 µM with RRE IIB, preference for RNA over DNA (27 fold), and selectivity of up to >75 fold against a panel of RRE IIB variants. Structure-activity studies suggest that the boronic acid moiety and “branching” in peptides are key structural features for efficient binding and selectivity for the folded RNA target. >BPBA1 was efficiently taken up by HeLa and A2780 cells. RNA-footprinting studies revealed that the >BPBA1 binding site encompasses a large surface area that spans both the upper stem as well as the internal loop regions of RRE IIB.