A Modular Approach to Synthetic RNA Binders of the Hepatitis C Virus Internal Ribosome Entry Site

Abstract

Natural products that target the RNA components of bacterial ribosomes, and thereby act as antibiotics that shut down microbial protein synthesis, have provided a rich source of inspiration for the design and synthesis of small molecule ligands directed at RNA targets.[1, 2] A prominent example of a privileged scaffold for RNA recognition occurring in natural aminoglycoside antibiotics is 2-deoxystreptamine (2-DOS),[3] which contains a rigid framework of hydrogen bond donors among which the rigid cis-1,3 arrangement of amino groups is responsible for selective interaction with structural motifs in RNA targets (Figure 1).[4] In an approach to reduce the complexity of chemical library synthesis involving the highly functionalized 2-DOS scaffold, we have recently developed the 3,5-diaminopiperidine heterocycle (DAP) as a structural mimetic of the RNA-recognizing pharmacophore of the 2-DOS scaffold (Figure 1). Structure-guided design had been applied to discover a series of antibacterial DAP-triazine derivatives that act on the same ribosomal RNA target as the natural aminoglycoside antibiotics which initially served as the inspiration for the conception of the DAP compounds.[5, 6]