Inpharma 1386 - 10 May 2003 New directions in drug discovery: targeting RNA "The development of RNA interference as a major platform for high-throughput target validation has put RNA in the spotlight of drug discovery research. RNA is not only used as a tool for target validation, but is also being developed as a therapeutic", say Dr Guido Zaman and colleagues from N.V. Organon, Oss, The Netherlands. They note that historically, drug discovery has focussed on compounds that modulate proteins, such as receptor agonists or antagonists, or on compounds that inhibit or stimulate protein-protein interactions. "The intermediary product between gene and protein, consisting of mRNA, is largely unexplored", say Dr Zaman and colleagues. They go on to say that several existing therapeutics target RNA, such as the aminoglycoside antibacterials. These agents bind to bacterial rRNA as well as to a variety of other RNA structures, including the Rev protein response element in the envelope gene of HIV-1 and the transactivation-responsive element of HIV-1 RNA, say Dr Zaman and colleagues. In addition, a variety of synthetic molecules, such as heterocycles, polycations and intercalators, also bind to RNA specifically, note Dr Zaman and colleagues. They go on to say that the use of X-rays and nuclear magnetic resonance spectroscopy has enabled researchers to identify several potential target sites in mRNA molecules, including the binding sites of proteins that regulate mRNA translation and stability. Furthermore, several technologies have been developed to screen for small compounds that target RNA. However, another approach is to screen at the RNA level well-established protein targets that have so far been unsuccessful, say Dr Zaman and colleagues. In their opinion, this approach is an economical one as it can be built upon existing biological knowledge and will not require the expensive functional genomics studies essential for the discovery of new drug targets. Dr Zaman and colleagues also note that RNA offers new opportunities for drug development, such as the targeting 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 1 Inpharma 10 May 2003 No. 1386 1173-8324/10/1386-0001/$14.95 Adis © 2010 Springer International Publishing AG. All rights reserved

New directions in drug discovery: targeting RNA

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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