Synthesis and biological validation of N7-(4-chlorophenoxyethyl) substituted dinucleotide cap analogs for mRNA translation

Jun 20, 2013Bioorganic & medicinal chemistry

Making and testing modified RNA caps that may improve protein production

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Abstract

New cap analogs showed 77% and 76% capping efficiency, surpassing the standard cap analog's 63%.

N(7)-(4-chlorophenoxyethyl) substitution enhances capping efficiency for T7 RNA polymerase.
The new cap analogs are effective substrates for transcription processes.
One analog resulted in mRNA translation that was approximately 1.64-fold more efficient compared to the standard cap.
The other analog demonstrated approximately 0.72-fold less translation efficiency than the standard cap.
The lower translation activity of one analog may relate to its stability.

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Design, synthesis and biological validation of dinucleotide cap analogs, N(7)-(4-chlorophenoxyethyl)-G(5')ppp(5')G (5a) and N(7)-(4-chlorophenoxyethyl)-m(3'-O)G(5')ppp(5')G (5b) are reported. The effect of N(7)-(4-chlorophenoxyethyl) substitution on cap analogs has been evaluated with respect to its in vitro transcription by using T7 RNA polymerase capping efficiency, and translational activity. The gel shift assay indicates that the new cap analogs (5a, 5b) showed 77% and 76% capping efficiency respectively, whereas the standard cap analog, m(7)G(5')ppp(5')G has a capping efficiency of 63%. The capping efficiency experiment clearly demonstrates that the N(7)-modified analogs are good substrate for T7 RNA polymerase. It is noteworthy that the mRNA poly(A) capped with N(7)-(4-chlorophenoxyethyl)-m(3'-O)G(5')ppp(5')G (5b) was translated ∼1.64-fold more efficiently, while compound (5a) was translated ∼0.72-fold less efficiently than mRNA capped with standard cap analog. The observed low translation activity for (5a) could be due to stability in the form of dinucleotide cap analogs. Based on the substrate compatability of the N(7) modification in dinucleotide form, these new analogs may be used for structure function studies as well as protein production.

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Synthesis and biological validation of N7-(4-chlorophenoxyethyl) substituted dinucleotide cap analogs for mRNA translation

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