Design of RNA-targeting macrocyclic peptides

Abstract

RNA structures play a pivotal role in many biological processes and the progression of human disease, making them an attractive target for therapeutic development. Often RNA structures operate through the formation of complexes with RNA-binding proteins, however, much like protein-protein interactions, RNA-protein interactions span large surface areas and often lack traditional druggable properties, making it challenging to target them with small molecules. Peptides provide much greater surface areas and therefore greater potential for forming specific and high affinity interactions with RNA. In this chapter, we discuss our approach for engineering peptides that bind to structured RNAs by highlighting methods and design strategies from previous successful projects aimed at inhibiting the HIV Tat-TAR interaction and the biogenesis of oncogenic microRNAs.

Keywords: Beta-hairpins; Macrocyclic peptides; NMR; Peptidomimetics; RNA; Structure-based design.