Inhibition of avian myeloblastosis virus reverse transcriptase by diphosphates of acyclic phosphonylmethyl nucleotide analogues

Abstract Diphosphates of N -(2-phosphonylmethoxyethyl) derivatives of heterocyclic bases were studied in the endogenous oligo(dT) 12–18 primed reaction of reverse transcriptase from detergent-disrupted AMV(MAV) retrovirions. These diphosphates (analogues of nucleotide 5′-triphosphates) exhibited an inhibitory activity towards reverse transcriptase. This inhibitory activity was dependent on the character of the heterocyclic base and decreased in the order: 2-aminoadenine . adenine > guanine ⪢ cytosine ⪢ thymine > uracil. The 2-aminoadenine derivative was more potent than either AZT-TP or ddTTP, while PMEApp had approximately the same potency as the two reference compounds (IC 50 ≈ 1 μM at 20 μM competing substrate). This finding is consistent with the antiviral activity of the parent nucleotide analogues against retroviruses (including HIV).