ANTIVIRAL ACTIVITIES OF 9-R-2-PHOSPHONOMETHOXYPROPYL ADENINE (PMPA) AND BIS(ISOPROPYLOXYMETHYLCARBONYL)PMPA AGAINST VARIOUS DRUG-RESISTANT HUMAN-IMMUNODEFICIENCY-VIRUS STRAINS

9-R-2-Phosphonomethoxypropyl adenine (PMPA) is an acyclic nucleoside p hosphonate analog that has demonstrated efficacy against human immunod eficiency virus (HIV). We recently described the synthesis, metabolism , and biological activities of bis(isopropyloxymethylcarbonyl)PMPA [bi s(poc)PMPA] as an orally bioavailable prodrug for PMPA. Among a large panel of drug-resistant HIV type 1 variants, only the K65R virus was r esistant to PMPA, K65R virus also showed reduced susceptibility to bis (poc)PMPA, although the prodrug could still inhibit these viruses at s ubmicromolar, nontoxic concentrations. Among a panel of seven primary clinical isolates from patients with diverse treatment histories, only one isolate showed reduced susceptibility to PMPA and was found to ca rry three mutations (M41L, T69N, R73K) in its reverse transcriptase ca talytic domain.