MARKED INHIBITORY ACTIVITY OF MASKED ARYLOXY AMINOACYL PHOSPHORAMIDATE DERIVATIVES OF DIDEOXYNUCLEOSIDE ANALOGS AGAINST VISNA VIRUS-INFECTION

Lipophilic masked aryloxyaminoacylphosphoramidate derivatives of 2',3' -dideoxynucleoside (ddN) analogues with potent anti-HIV activity (i.e. , stavudine [d4T], azidothymidine [AZT], dideoxycytidine [ddC], 3'thio -2',3'-dideoxy cytidine [3TC], dideoxyadenosine [ddA], and 2',3'-dideh ydro-2',3'-dideoxyadenosine [d4A]) activity were evaluated for their a ctivity against visna virus (VV) in sheep choroid plexus (SCP) cells. The activity of several prodrug derivatives against VV proved markedly superior to that of the corresponding free ddN analogues. In particul ar, the d4A and ddA prodrug derivatives were exquisitely inhibitory in this model system (50% effective concentration [EC50], less than or e qual to 0.003 mu M), and their anti-VV potency exceeded by at least 20 0-fold the antiviral potency of the corresponding free nucleosides. Ma rked differences were noted in the anti-VV potencies of several of the test compounds depending on the nature of the amino acid linked to th e 5'-phosphate moiety, the nature of the nucleoside, or both. In view of the stability of the prodrugs in lamb serum, the VV infection model in lambs may be considered highly useful for investigating the in viv o antiretroviral efficacy of these type of drugs, particularly the d4T , ddA, and d4A prodrug derivatives.