2`,5`-Oligoadenylate (2-5A) derivatives have been designed to act distal to the human immunodeficiency virus-1 (HIV-1)-induced blockade in the 2-5A synthetase/RNase L antiviral pathway. Stereochemical modification of individual internucleotide linkages of the 2-5A molecule was accomplished by phosphoramidite and phosphotriester chemical syntheses. Phosphorothioate/phosphodiester trimer and tetramer 2-5A derivatives revealed differences in the stereodynamics of activation of RNase L and inhibition of HIV-1 replication. The first and second internucleotide linkages are critical for activation of recombinant, human RNase L; A(R)ApA, A(S)ApA and ApA(R)A are agonists (IC = 2 10, 2 10, and 8 10M); ApA(S)A is an antagonist. The second and third internucleotide linkages are crucial for activation of murine RNase L; ApA(R)A, ApA(R)ApA, and ApApA(R)A are agonists (IC = 5 10M); ApA(S)A, ApA(S)ApA, and ApApA(S)A are antagonists. Inhibition of HIV-1-induced syncytia formation by the phosphorothioate/phosphodiester derivatives is specific for derivatives with substitution at the 2`,3`-terminus. ApA(R)A, ApA(S)A, ApApA(R)A, and ApApA(S)A are potent inhibitors of HIV-1-induced syncytia formation (80-, 10-, 40-, and 15-fold more inhibitory, respectively, than solvent control). HIV-1 infection results in enhanced uptake and accumulation of ApA(R)A and ApA(S)A (7- and 10-fold, respectively). These stereochemically modified 2-5A derivatives are taken up preferentially by HIV-1-infected cells and show promise in anti-HIV-1 chemotherapy.

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