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Our findings can help expand strategies for rationally optimizing siRNA activity via chemical modifications of nucleotide bases.A key approach for improving siRNA efficacy is chemical modifications. Through an in silico screening of modifications at the 5'-end nucleobase of the guide strand, an adenine-derived compound called 6-(3-(2-carboxyethyl)phenyl)-purine (6-mCEPh-purine) was identified to improve the RNAi activity in cultured human cells and in vivo mouse models. Nevertheless, it remains unclear how this chemical modification enh
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