DESIGN AND SYNTHESIS OF RNA-SPECIFIC GROOVE-BINDING CATIONS - IMPLICATIONS FOR ANTIVIRAL DRUG DESIGN

As as initial step in the design of structure-specific RNA-interactive molecules as potential antiviral agents, we have focused on the synth esis of molecules that exhibit strong and preferential binding to dupl ex RNA. A series of polycationic ligands have been synthesized, and th e degree of preferential binding to RNA has initially been determined by thermal denaturation (Delta T-m) with both RNA poly(A) poly(U) an d DNA poly(dA).poly(dT) polymers at a variety of pH values. Seven co mpounds from the series exhibit a substantial degree of RNA-selective binding. The relatively high Delta T-m values obtained suggest a speci fic mode of interaction between these ligands and the RNA helix. By co ntrast, the much lower Delta T-m values with poly(dA) poly(dT) DNA ref lect a more nonspecific interaction mode, A viscometric titration stud y with poly(A) poly(U) confirms that they do not bind by intercalation . The results, combined with the known structure and electronegative p otential of duplex RNA, suggest that these molecules bind in the major groove via specific electrostatic and/or hydrogen-bonded interactions .