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Exploring chemical modifications for sirna therapeutics: a structural and functional outlook

DSpace at IIT Bombay

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Title Exploring chemical modifications for sirna therapeutics: a structural and functional outlook
 
Creator SHUKLA, S
SUMARIA, CS
PRADEEPKUMAR, PI
 
Subject chemical modifications
drug delivery
protein structures
rna interference
small interfering rnas
small interfering rna
double-stranded-rna
induced silencing complex
cultured-mammalian-cells
in-vivo delivery
argonaute2 paz domain
a-aeolicus argonaute
off-target
crystal-structure
gene-expression
 
Description RNA interference (RNAi) is a post-transcriptional gene silencing mechanism induced by small interfering RNAs (siRNAs) and micro-RNAs (miRNAs), and has proved to be one of the most important scientific discoveries made in the last century. The robustness of RNAi has opened up new avenues in the development of siRNAs as therapeutic agents against various diseases including cancer and HIV. However, there had remained a lack of a clear mechanistic understanding of messenger RNA (mRNA) cleavage mediated by Argonaute2 of the RNA-induced silencing complex (RISC), due to inadequate structural data. The X-ray crystal structures of the Argonaute (Ago)-DNA-RNA complexes reported recently have proven to be a breakthrough in this field, and the structural details can provide guidelines for the design of the next generation of siRNA therapeutics. To harness siRNAs as therapeutic agents, the prudent use of various chemical modifications is warranted to enhance nuclease resistance, prevent immune activation, decrease off-target effects, and to improve pharmacokinetic and pharmacodynamic properties. The focus of this review is to interpret the tolerance of various chemical modifications employed in siRNAs toward RNAi by taking into account the crystal structures and biochemical studies of Ago-RNA complexes. Moreover, the challenges and recent progress in imparting druglike properties to siRNAs along with their delivery strategies are discussed.
 
Publisher WILEY-V C H VERLAG GMBH
 
Date 2011-10-12T12:50:58Z
2011-12-15T09:16:07Z
2011-10-12T12:50:58Z
2011-12-15T09:16:07Z
2010
 
Type Review
 
Identifier CHEMMEDCHEM,5(3)328-349
1860-7179
http://dx.doi.org/10.1002/cmdc.200900444
http://dspace.library.iitb.ac.in/xmlui/handle/10054/13775
http://hdl.handle.net/100/3011
 
Language en