New directions in drug discovery: targeting RNA

Inpharma 1386 - 10 May 2003

New directions in drug discovery:targeting RNA

"The development of RNA interference as a majorplatform for high-throughput target validation has putRNA in the spotlight of drug discovery research. RNA isnot only used as a tool for target validation, but is alsobeing developed as a therapeutic", say Dr Guido Zamanand colleagues from N.V. Organon, Oss, TheNetherlands.

They note that historically, drug discovery hasfocussed on compounds that modulate proteins, such asreceptor agonists or antagonists, or on compounds thatinhibit or stimulate protein-protein interactions. "Theintermediary product between gene and protein,consisting of mRNA, is largely unexplored", say DrZaman and colleagues.

They go on to say that several existing therapeuticstarget RNA, such as the aminoglycoside antibacterials.These agents bind to bacterial rRNA as well as to avariety of other RNA structures, including the Revprotein response element in the envelope gene of HIV-1and the transactivation-responsive element of HIV-1RNA, say Dr Zaman and colleagues. In addition, a varietyof synthetic molecules, such as heterocycles,polycations and intercalators, also bind to RNAspecifically, note Dr Zaman and colleagues.

They go on to say that the use of X-rays and nuclearmagnetic resonance spectroscopy has enabledresearchers to identify several potential target sites inmRNA molecules, including the binding sites of proteinsthat regulate mRNA translation and stability.Furthermore, several technologies have been developedto screen for small compounds that target RNA.However, another approach is to screen at the RNA levelwell-established protein targets that have so far beenunsuccessful, say Dr Zaman and colleagues. In theiropinion, this approach is an economical one as it can bebuilt upon existing biological knowledge and will notrequire the expensive functional genomics studiesessential for the discovery of new drug targets. DrZaman and colleagues also note that RNA offers newopportunities for drug development, such as thetargeting of noncoding RNA sequences.Zaman GJR, et al. Targeting RNA: new opportunities to address drugless targets.Drug Discovery Today 8: 297-306, No. 7, Apr 2003 800925801

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Inpharma 10 May 2003 No. 13861173-8324/10/1386-0001/$14.95 Adis © 2010 Springer International Publishing AG. All rights reserved