2',5'-OLIGOADENYLATE - ANTISENSE CHIMERAS SYNTHESIS AND PROPERTIES

We have synthesized a novel bioconjugate which joins an antisense olig onucleotide to a unique and potent inhibitor of translation, p(n)5'A2' (p5'A2')(m)p5'A(2-5A). Two residues of 4-hydroxybutyl phosphate were e mployed as linkers to attach the 2',5'-oligoadenylate moiety through i ts 2'-terminus to the 5'-terminus of the chosen antisense sequence, (d T)20. The syntheses were carried on a solid support according to the p hosphite triester method of DNA synthesis (Letsinger, R. L., and Lunsf ord, W. B. (1976) J. Am. Chem. Soc. 98, 3655-3661; Beaucage, S. L., an d Caruthers, M. H. (1981) Tetrahedron Lett. 22, 1859-1862). The genera ted 2-5A antisense chimeras retained both the ability of the 2-5A mole cule to activate the 2-5A-dependent RNase as well as the ability of th e oligo(dT) moiety to hybridize to the complementary poly(A). Moreover , the chimera, when annealed to its target nucleic acid sequence, was still effectively bound to the 2-5A-dependent nuclease. The methodolog y described represents a new approach to the selective modulation of m RNA expression.