AIDSWEEKLY Plus, 10 June 1996
Daniel J. DeNoon, Senior Editor

A new acyclic nucleotide is just as potent - and, in laboratory studies, nine times less toxic - than adefovir (PMEA).

PMEA [9-(2-phosphonylmethoxyethyl)-adenine] is the prototypic compound for a new class of drugs active against HIV, herpesviruses, and hepatitis viruses. Unlike nucleoside analogs (AZT, ddI, ddC, d4T, etc.), these nucleotide analogs are already in their active form and do not require intracellular processing for activation.

An orally bioavailable form of PMEA, bis-POM-PMEA or adefovir dipivoxil, is being tested for anti-HIV and anti- hepatitis B efficacy in clinical trials.

Now researchers at the U.K.'s Medical Research Council have found that the compound 9-[2-methylidene-3- (phosphonylmethoxy)propyl]-guanine (MDL 74,968) works as well as PMEA but is less toxic to human cells. They reported their findings in the journal Antimicrobial Agents and Chemotherapy ("MDL 74,968, A New Acyclonucleotide Analog: Activity Against Human Immunodeficiency Virus In Vitro and in the hu-PBL- SCID.Beige Mouse Model of Infection," Antimic Ag Chem, 1996;40(5):1072-7).

"MDL 74,968 had anti-HIV activity similar to that of PMEA in vitro, including antiviral activity in human PBMCs infected with a range of clinical HIV isolates," wrote MRC researcher C.G. Bridges and colleagues.

"These promising findings suggest that an orally bioavailable prodrug of MDL 74,968 should be developed for the treatment of HIV infection."

Researchers at Marion Merrell Dow, Strasbourg, France, discovered MDL 74,968 in a search for novel acyclonucleotide analogs with increased antiviral selectivity (Casara et al., Bioorg Med Chem Lett, 1995;5:1275-80). MDL 74,968, was as effective as PMEA against HIV-1, HIV-2, and human cytomegalovirus (CMV).

Bridges et al. found that MDL 74,968 was not toxic in mice when delivered intraperitoneally in doses up to 1600 mg/kg body weight, or when delivered intravenously in doses up to 500 mg/kg.

Immunodeficient mice reconstituted with elements of the human immune system and infected with HIV showed a significant reduction in symptoms of infection when treated for five days with continuous subcutaneous infusion of 20 mg/kg/day MDL 74,968. Virus load in these mice was also significantly reduced (but not eliminated) after treatment.

Pretreatment of mice with MDL 74,968 did not prevent them from becoming infected with HIV.

The corresponding author for this study is C.G. Bridges, MRC Collaborative Centre, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, United Kingdom. Phone: 44 181 906 3811. Fax: 44 181 906 1395. Email: (g-bridge@nimr.mrc.ac.uk).

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