Over the last few decades, bacterial resistance to antibiotics has become a major problem.  This is, due in part, because we have focused our attention primarily on proteins as drug targets. Highly structured RNA molecules present excellent targets for new classes of antibiotics. Riboswitches are segments in untranslated region of mRNA that control gene expression upon binding to small ligands. Our lab is interested in the synthesis of novel guanine analogs with modifications at both the C2 and C6 positions of the purine ring.  These analogs have the potential of tightly binding to the 5'-untranslated region of xanthine phosphoribosyl transferase (xpt) riboswitch mRNA. High-resolution structure of xpt riboswitch shows that there maybe additional binding space where it may be possible to add functional groups without significantly disrupting ligand binding to the existing pocket. Functional groups at C2 and C6 position of the purine ring can facilitate additional H-bonds with nucleotides near the binding pocket of xpt mRNA potentially yielding stronger ligand-mRNA interactions.  We have conducted in vivo assays on a library of compounds using beta galactosidase as a reporter.  To our surprise, we have found that one of the synthesized compounds yields galactosidase expression in much higher amounts than the solvent control.  Molecular dynamics simulations show that some of our compounds bind to xpt RNA with a greater free energy and number of H-bonds than cognate guanine ligand.

Binding interactions of purine analogs with xanthine phosphoribosyltransferase mRNA

244th National Meeting (2012)

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