A modular approach to synthetic RNA binders of the hepatitis C virus internal ribosome entry site.

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. 2] A prominent example of a privileged scaffold for RNA recognition occurring in natural aminoglycoside antibiotics is 2-deoxystreptamine (2-DOS), 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). In an approach to reduce the complexity of chemical library synthesis that involves 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. Here, we describe the synthesis of a novel class of modular ligands (1) that contain the DAP scaffold as the key moiety for RNA recognition in nonribosomal targets (Figure 1). Screening of modular DAP ligands against the subdomain IIa, an RNA target in the internal ribosome entry site (IRES) of hepatitis C virus (HCV) (Figure 1), revealed a set of N-amido substituted aamino acid conjugates of DAP (2) as micromolar binders of this RNA. We had previously shown that ligand-induced conformational change in the subdomain IIa RNA disrupts the function of the IRES and blocks viral protein synthesis ; this ultimately leads to inhibition of HCV in infected cells. The common building block 4 used in the synthesis of the modular DAP compounds 2 was obtained from 2-chloro-3,5-dinitro-pyridine (3) following an established route, which required, in the last step, high-pressure hydrogenation to reduce the pyridine (Scheme 1). As the yield in this transformation critically depends on the hydrogen pressure (>1000 psi), we sought to employ an alternative reduction procedure. Among the explored methods, neither transformation of the pyridine