Researchers at Isis Pharmaceuticals Inc. have created modifiedantisense compounds that potently block a common canceroncogene in vitro, they report in this week's edition of theJournal of Biological Chemistry.
The molecules have backbones forged from linkages that resistbreakdown within the cell. Each end of the chemical chain hasbeen accessorized to tightly grasp RNA carrying the geneticmessage of the Ha-ras oncogene. The middle of the molecule isiced with sugars similar to those contained by DNA. Thatportion attracts the chemical clipper RNase H, which leaves theIsis molecule intact but snips the RNA into useless pieces so itcannot direct formation of cancer-causing proteins.
Backbones such as this phosphorothioate one have beendescribed previously. The scientists tested the effects ofaltering sugar components in the 17-subunit molecule with 2-prime O-methyl groups and other modifications, such as 2-prime fluoro dA. Altered compounds bound their target betterthan unmodified oligonucleotides.
Interspersing an interior segment of at least five subunits thatbear deoxy sugar groups was necessary, however, for thetarget to be enzymatically degraded. RNase H, present innuclear extract of the HeLa line of human cancer cells used, isthought to play a natural role in DNA replication by cleavingthe RNA strand of RNA-DNA complexes.
The Ha-ras oncogene itself is a mutation of a normal geneinvolved in the regulation of cell growth.
The authors suggest that the small size of the compound andthe potential of using alterations that are compatible with thecontent of cell membranes could facilitate its use in drugs, ascould its stability and potency.
In addition to this paper by Isis researcher Brett Monia andcolleagues, the Carlsbad, Calif., company also recentlyannounced issuance of a U.S. patent for novel nucleosides usedin synthesis of enzyme-resistant oligonucleotides.
U.S. Patent No. 5,223,618, for a 4-prime desmethyl nucleosideanalog, grants Isis protection for making a novel class ofcompounds, oligonucleosides, that use an ethylene glycol inplace of a phosphate in the backbone, resulting in a compoundthat resists enzyme degradation and lacks a negative charge.
The company (NASDAQ:ISIP) has its first oligonucleotide-baseddrug, ISIS 2105, in a Phase II trial for treatment of humanpapillomavirus infection.
-- Nancy Garcia Associate Editor
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