Isis Pharmaceuticals Inc. is using its novel oligonucleotide-binding technique to target one of the key regulatory RNAregions of HIV.

Isis reported in Science its new approach, called pseudo-half-knot formation, and its use in the design of antisenseoligonucleotides to target regions of viral or cellular RNA.

According to Christopher Mirabelli, Isis' senior vice president,RNA consists of complex secondary structures, such as stemsand loops, that are difficult to bind with antisenseoligonucleotides because the RNA itself has precluded theability to target molecules to the stem structure of RNA stemloops.

Isis reports that by binding to the HIV RNA using the psuedo-half-knot formation, the viral regulatory protein wasdisplaced from its natural binding site. As a result, themodified protein structure no longer recognized the stemstructure and no longer bound to it, thus interrupting the viralreplication process.

The Carlsbad, Calif., company is involved in the discovery anddevelopment of novel therapeutic products based on antisenseoligonucleotides. It has a series of patents covering itspsuedo-half-knot formation technique, including one thatcovers the technique used in HIV RNA.

"The technique allows us to target many more regions on themRNA (messenger RNA) than before, when we were limited tobeing able to target only the single stranded RNAs," saidMirabelli. "The technique gives us a new set of parameters thatwe can now design into our compounds."

-- Michelle Slade Associate Editor

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