2-vinyl-4-6-diamino-1-3-5-triazine and Myotonic-Dystrophy

The alkylation of the specific higher-order nucleic acid structures is of great significance in order to control its function and gene expression. In this report, we have described the T-T mismatch selective alkylation with a vinyldiaminotriazine (VDAT)-acridine conjugate. The alkylation selectively proceeded at the N3 position of thymidine on the T-T mismatch. Interestingly, the alkylated thymidine induced base flipping of the complementary base in the duplex. In a model experiment for the alkylation of the CTG repeats DNA which causes myotonic dystrophy type 1 (DM1), the observed reaction rate for one alkylation increased in proportion to the number of T-T mismatches. In addition, we showed that primer extension reactions with DNA polymerase and transcription with RNA polymerase were stopped by the alkylation. The alkylation of the repeat DNA will efficiently work for the inhibition of replication and transcription reactions. These functions of the VDAT-acridine conjugate would be useful as a new biochemical tool for the study of CTG repeats and may provide a new strategy for the molecular therapy of DM1.

Topics: Acridines; Alkylation; Base Pair Mismatch; Base Pairing; Base Sequence; DNA; DNA Replication; DNA-Directed DNA Polymerase; DNA-Directed RNA Polymerases; Humans; Molecular Targeted Therapy; Myotonic Dystrophy; Thymidine; Transcription, Genetic; Triazines; Trinucleotide Repeats; Vinyl Compounds