Arginine-aminoglycoside conjugates that bind to HIV transactivation responsive element RNA in vitro

HIV gene expression is crucially dependent on binding of the viral Tat prot ein to the transactivation RNA response element. A number of synthetic Tat- transactivation responsive element interaction inhibitors of peptide/peptoi d nature were described as potential antiviral drug prototypes. We present a new class of peptidomimetic inhibitors, conjugates of L-arginine with ami noglycosides. Using a gel-shift assay and affinity chromatography on an L-a rginine column we found that these compounds bind specifically to the trans activation responsive element RNA in vitro with K-d values in the range of 20-400 nM, which is comparable to the K-d Of native Tat bound to the transa ctivation responsive element (10-12 nM), Confocal microscopy studies demons trated that fluorescein-labelled conjugate penetrates into live cells, High affinity to the transactivation responsive element, low toxicity, and rela tive simplicity of synthesis make these compounds attractive candidates for antiviral drug design. (C) 1999 Federation of European Biochemical Societi es.