Kinetics of inhibition of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase by the novel HIV-1-specific nucleoside analogue [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro-5 “- (4”-amino-1“,2”-oxathiole-2“,2”-dioxide)thymine (TSAO-T).

Abstract

2',5'-Bis-O-(tert-buty1dimethylsilyl)-~-~-ribofur-anosy1]-3~-~pi~o-5''-(4''-amino-1'',2''-oxathio1e-2'', 2"-dioxide)thymine (TSAO-T) is a representative of a novel class of nucleoside analogues that are endowed with a potent and specific activity against human immunodeficiency virus (HIV) type 1 and are targeted at the HIV-1 reverse transcriptase (RT).Inhibition of HIV-1 RT by TSAO-T was reversible and noncompetitive with respect to dGTP as the substrate and poly(C).oligo(dG) as the template/primer.In contrast with the nonnucleoside derivatives tetrahydroimidazo-[4,5,l-jk][l,4]-benzodiazepin-2(12jr)-thione (TIBO) (R-82150), nevirapine (BI-RG-587) and the HEPT derivative I-HEPU-SdM, TSAO-T was not inhibitory to HIV-1 RT in the presence of other homopolymeric template/primers.It did not interfere with the DNAdependent DNA polymerase function of HIV-1 RT, HIV-2 RT, herpes simplex virus type 1 DNA polymerase, or Taq polymerase.However, TSAO-T proved inhibitory to the HIV-1 RT reaction primed by Escherichia coli 16S/23S rRNA, irrespective of the nature of the radiolabeled 2'-deoxynucleotide 5'-triphosphate (dNTP) used.TSAO-T does not act as a DNA chain terminator.It interacts with HIV-1 RT at a nonsubstrate (dNTP)-binding site.Various compounds have been reported as potent and selective inhibitors of human immunodeficiency virus (HIV)' replication in cell culture.The 2',3'-dideoxynucleoside analogues (1-7) and acyclic nucleoside phosphonate derivatives