Silicon Investor (SI) -- The First Internet Community

STOCKTALK

We've detected that you're using an ad content blocking browser plug-in or feature. Ads provide a critical source of revenue to the continued operation of Silicon Investor. We ask that you disable ad blocking while on Silicon Investor in the best interests of our community. If you are not using an ad blocker but are still receiving this message, make sure your browser's tracking protection is set to the 'standard' level.

Biotech / Medical : VGNX -- Variagenics, Inc. -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (124)	2/26/2002 12:41:53 AM
From: scaram(o)uche	Respond to of 269

Proc Natl Acad Sci U S A 2002 Feb 19;99(4):1882-7 Forced engagement of a RNA/protein complex by a chemical inducer of dimerization to modulate gene expression. Harvey I, Garneau P, Pelletier J. Department of Biochemistry and McGill Cancer Center, McIntyre Medical Sciences Building, McGill University, Montreal, QC, Canada H3G 1Y6. A general strategy is described for forcing the engagement of an RNA/protein complex by using small-molecule ligands. A bivalent molecule was created by linking a protein-binding ligand to an RNA-binding ligand. On presentation of the chemical inducer of dimerization to the RNA by the protein, cooperative binding ensued, resulting in higher-affinity complexes. When the chemical inducer of dimerization was used to target the protein to an mRNA template, the resulting RNA/protein complex was sufficiently stable to inhibit mRNA translation. This approach provides a logic to modulate gene expression by using small-molecule ligands to recruit protein surfaces to mRNAs. ******************* from today's BioCentury (thanks, R!)......... “The flexible nature of RNA allows it to change shape, making it difficult to design small molecules that will bind and remain bound with high affinity. Also, many binding pockets either appear or disappear depending on what proteins are bound to the RNA at a given time,” said Vincent Stanton Jr., vice president and principal scientist at Variagenics Inc. Researchers at McGill University in Montreal avoided this problem by creating a chemical inducer of dimerization (CID), a bivalent molecule that recognizes mRNA at a specific sequence that also binds to a specific protein, in essence gluing the mRNA and proteins together. Specifically, the researchers showed that a tobramycin-based CID caused a 5- to 10-fold reduction in the production of reporter protein in vitro. Though their work is the first peer reviewed publication using the CID technology, VGNX (Cambridge, Mass.) filed a European patent application covering the CID methodology in 2000. The McGill researchers subsequently initiated CID research at the company’s suggestion, though VGNX did not fund the study. The binding constant of the RNA/CID/protein complex was in the nanomolar range, which is much better than the affinity of tobramycin for the RNA itself, showing that the CID’s contribution to the complex is critical. Without it, no protein/RNA complex would exist at all. The simultaneous binding of the CID to the protein and mRNA puts the two in close proximity, allowing the RNA to not only bind to the CID, but to wrap around the protein as well. “The cooperativity in binding is extremely important because it attenuates the ability of the mRNA to bind to the ribosome,” Stanton told BioCentury. The article showed that the tobramycin-based CID inhibited translation by disrupting the formation of the 80S ribosome, which is necessary for proper protein translation. The strategy theoretically could allow small molecules to be designed to disrupt the production of any protein, but Stanton noted that the application of CIDs towards therapeutics is still in development. “It is clear that this will not work with every mRNA/protein pair and it will be necessary to identify cellular proteins that interact cooperatively with RNA and develop CIDs that bind with a high affinity to them,” he said. Stanton added that though VGNX is doing CID research, the company’s major focus remains pharmacogenomics. (doesn't sound like it's high priority stuff)