ANTI-HIV ACTIVITY OF MDL-74968, A NOVEL ACYCLONUCLEOTIDE DERIVATIVE OF GUANINE - DRUG-RESISTANCE AND DRUG-COMBINATION EFFECTS IN-VITRO

MDL 74968 2-methylidene-3-(phosphonomethoxy)propyl]guanine), a novel a cyclonucleotide derivative of guanine, inhibited human immunodeficienc y virus type 1 (HIV-1) replication in vitro with activity comparable t o that of adefovir (PMEA; 9-(2-phosphonomethoxyethyl)adenine). MDL 749 68 was investigated in combination with two licensed nucleoside analog ues, zidovudine and didanosine, using a cell viability assay, and drug interactions were evaluated by the isobologram technique, by calculat ing combination indices and by the MacSynergy(TM) program. Inhibition of HIV-1 replication was only additive in both cases, MDL 74968 had eq uivalent antiviral activity against strains of HIV-1(HXB2) engineered to have mutations which conferred resistance to the nucleoside analogu es lamivudine, didanosine and zidovudine and the non-nucleoside inhibi tor of reverse transcriptase (RT) nevirapine, as against the wild type strain, Continued passage of HIV-1(RF) in C8166 cells in the presence of MDL 74968 for 5 months (30 passages) failed to select drug resista nt mutants. Continued passage of virus in the presence of the same con centration of adefovir for the same length of time selected a virus in a single culture, which was 3-fold resistant to adefovir and cross-re sistant to MDL 74968. Genotypic characterization of this virus reveale d a lysine to arginine exchange (AAA to AGA) at position 65 in the RT gene, This virus was not cross-resistant to either zidovudine or nevir apine but showed reduced sensitivity to zalcitabine, didanosine and la mivudine. Continued passage of HIV-1(RF) in the presence of nevirapine or zidovudine, using similar experimental protocols selected drug res istant viruses after eight and 17 passages, respectively, but these vi ruses remained sensitive to adefovir and MDL 74968.