ALTERNATING ALPHA,BETA-OLIGOTHYMIDYLATES AS MODEL ANTISENSE MOLECULES

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Alternating alpha,beta-oligothymidylates with alternating (3'-3')- and (5'-5')-internucleotidic phosphodiester linkages have been synthesized to evaluate the stability of these oligonucleotide analogues to nucleases and their hybridization abilities. It was found that these oligomers hybridized to their complementary beta-oligodeoxyriboadenylate as tightly as phosphorothioate oligomers. The alpha,beta- oligothymidylates were also more resistant to the nucleolytic activity of S1 nuclease than that of the phosphorothioate and beta- oligothymidylates. During the last months of his tenure in our laboratory Dr. Koga has synthesized 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 preparation of alpha-deoxyguanosine and its phosphoramidite has been particularly difficult. Since the departure of Dr. Koga in January 1992, this project has not progressed. A replacement for Dr. Koga has not, as yet, been approved. More data are required to complete the study of this interesting class of oligonucleotides achiral at phosphorus. Specifically, it would be worth gathering various physico- chemical properties (thermal denaturation and CD analysis) and extended nucleolytic resistance data before applying these oligonucleotide analogues to antisense experiments.