Modified nucleoside 5'-triphosphonates as a new type of antiviral agents.

Abstract

Abstract The design of dNTP analogs with increased stability in vivo could produce a new group of highly effective inhibitors of HIV reproduction. The advantages of such compounds would be as follows: (i) Independence on the phosphorylation process catalyzed by intracellular enzymes, and direct inhibition of proviral DNA synthesis. (ii) The lack of the cell cycle effect on their activity. (iii) The ability to inhibit reverse transcription of the virus circulating in blood plasma. It is also desirable that such dNTP/rNTP analogs possess selective substrate properties towards viral enzymes and be hydrophobic enough to penetrate into the cell or be able to be bound by membrane proteins which would facilitate their transportation into cells. We present the biological evaluation of carbocyclic analogs of L-d4NTP of I-III types in cell-free systems with HIV and avian myeloblastosis reverse transcriptases, DNA polymerases α and β, terminal deoxynucleotidyl transferase, as well as in Rat1 cell culture infected by...