Synthesis and use of anti-reverse phosphorothioate analogs of the messenger RNA cap
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Abstract
New RNA cap analogs are disclosed containing one or more phosphorothioates groups. The analogs also contain modifications at the 2′-O position of 7-methylguanosine that prevent them from being incorporated in the reverse orientation during in vitro synthesis of mRNA and that hence are “anti-reverse cap analogs” (ARCAs). The ARCA modification ensures that the S atom is precisely positioned within the active sites of cap-binding proteins in both the translational and decapping machinery. The new S-ARCA analogs are resistant to in vivo decapping enzymes. Some S-ARCAs have a higher affinity for eIF4E than the corresponding analogs not containing a phosphorothioate group. When mRNAs containing the various S-ARCAs are introduced into cultured cells, some are translated as much as five-fold more efficiently than mRNAs synthesized with the conventional analog m7GpppG.
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Citations
67 Claims
- 1. A composition comprising
- 11. A composition comprising
- 21. A composition comprising
- 31. A composition comprising
- 41. A composition comprising
- 51. A composition comprising
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61. A composition comprising one or more compounds selected from the group consisting of
m27,2′ - -OGppspG;
m27,3′
-OGppspG;
m27,2′
-OGpppspG;
m27,3′
-OGpppspG;
m27,2′
-OGppsppG;
m27,3′
-OGppsppG;
m27,2′
-OGpspspG;
m27,3′
-OGpspspG;
m27,2′
-OGppspsG;
m27,3′
-OGppspsG;
bn7m2′
-OGppspG;
bn7m3′
-OGppspG;
bn7m2′
-OGpppspG;
bn7m3′
-OGpppspG;
bn7m2′
-OGppsppG;
bn7m3′
-OGppsppG;
bn7m2′
-OGpspspG;
bn7m3′
-OGpspspG;
bn7m2′
-OGppspsG; and
bn7m3′
-OGppspsG. - View Dependent Claims (62, 63, 64, 65, 66, 67)
- -OGppspG;
Specification