MDL-74,968, A NEW ACYCLONUCLEOTIDE ANALOG - ACTIVITY AGAINST HUMAN-IMMUNODEFICIENCY-VIRUS IN-VITRO AND IN THE HU-PBL-SCID.BEIGE MOUSE MODELOF INFECTION

The novel acyclonucleotide derivative of guanine, -[2-methylidene-3-(p hosphonomethoxy)propyl]guanine guanine (MDL 74,968), had antiviral act ivity comparable to those of 9-(2-phosphonomethoxyethyl) adenine (PMEA ) and 2',3'-dideoxyinosine against laboratory strains of both human im munodeficiency virus (HIV) types 1 and 2 cultured in MT-4 cells and se veral clinical HIV isolates cultured in human peripheral blood mononuc lear cells (PBMCs). MDL 74,968 was at least fourfold less toxic than P MEA to MT-4 cells or PBMCs, thereby producing a more favorable in vitr o selectivity index for the former compound. Studies of acute toxicity in CD-1 mice showed that MDL 74,968 was not toxic at doses of 1,600 m g/kg of body weight via the intraperitoneal route or at doses of 500 m g/kg via the intravenous route. Furthermore, no adverse effects of MDL 74,968 were apparent when mice were treated at doses of 200 mg/kg twi ce daily for 5 days. Treatment by continuous subcutaneous infusion of MDL 74,968 or PMEA at the daily dose of 20 mg/kg in the hu-PBL-SCID.be ige murine model of HIV infection significantly reduced the severity o f infection compared with that in placebo-treated controls. Quantitati on of virus recovery by endpoint titration of spleen cells in cocultur e with mitogen-activated PBMCs demonstrated that MDL 74,968 as well as PMEA significantly reduced the amount of virus (P < 0.02). Moreover, by using DNA extracted from spleens, the mean HIV:HLA PCR product rati o, which takes into account individual variation in immune system reco nstitution, were 0.50 and 0.40 for MDL 74,968 and PMEA treatments, res pectively, whereas animals receiving the placebo control had significa ntly higher levels of HIV proviral DNA (mean 0.78; P < 0.02). Taken to gether, these promising findings suggest that an orally bioavailable p rodrug of MDL 74,968 should be developed for the treatment of HIV infe ction.