OLIGOTHYMIDYLATES WITH ALTERNATING (3'-3') AND (5'-5') PHOSPHODIESTER LINKAGES

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The P.I. has designed oligothymidylates having alternating (3' to 3')- and (5' to 5')-internucleotidic phosphodiester linkages based on the assumption that these oligonucleotides may not be recognized as rapidly by nucleases as natural oligomers. The alternate substitution of an alpha- monodeoxyribonucleotide for a beta-monodeoxyribonucleotide in the (3' to 3')- and (5' to 5')-internucleotidic linkage motif was achieved to improve the hybridizing properties of the oligonucleotide analogues. Dr. Koga synthesized the required alpha-deoxyribonucleoside phosphoramidites and the alpha, beta-oligothymidylate analogues were prepared along with the other oligonucleotide analogues (phosphorothioates and alpha-oligothymidylates) and a complementary beta- oligodeoxyriboadenylate to instigate meaningful control experiments. Alternating alpha,beta-oligothymidylates with alternating (3' to 3')- and (5' to 5')-internucleotidic phosphodiester linkages hybridized to their complementary beta-oligodeoxyriboadenylate as tightly as the phosphorothioate oligomer. The alpha,beta-oligothymidylates represent an interesting class of oligonucleotide analogues achiral at phosphorus. Dr. Koga is currently synthesizing the four different alpha- deoxyribonucleoside phosphoramidites in an attempt to prepare an alpha, beta-oligonucleotide complementary to the mRNA encoded by the rev gene of HIV-1. The anti-HIV activity of the oligonucleotide analogue will be tested in chronically infected H9 cells in a collaborative effort with Dr. Mitsuya of NCI. The potential formation of a triple helix between an alpha,beta- oligothymidylate and a poly dA-poly dT duplex will also be investigated by electrophoretic mobility shift experiments on polyacrylamide gels.