Organic & Biomolecular Chemistry

Abstract

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 a ffi nities in the low micromolar range. In particular, BPBA1 had a K d 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 e ffi cient binding and selectivity for the folded RNA target. BPBA1 was e ffi ciently 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.