Kiefer LL, Furman PA, Painter GR, Liberman I, Hill EL, Borroto KB, Chu CK, Schinazi RF; International Conference on AIDS.

Int Conf AIDS. 1998; 12: 85 (abstract no. 12358).

Triangle Pharmaceuticals Inc., Durham, NC, USA.

OBJECTIVES: To compare the anti-HIV-1 activity of (-)-beta-D-2,6-diaminopurine dioxolane (DAPD) and dioxolane guanosine (DXG) and to determine the mechanism of action of DAPD. RESULTS: DAPD and its metabolite DXG are inhibitors of HIV-1 replication in vitro. The EC50 values against HIV-1 in MT2 cells for DAPD and DXG are 1.5 +/- microM and 0.005 +/- microM, respectively. DAPD is also active against hepatitis B virus in vitro (EC50 = 0.024 microM) and in the woodchuck model for hepatitis. The concentration of both drugs that inhibit cell growth by 50% is > 100 microM. We have shown that DAPD is deaminated by adenosine deminase to DXG and that deamination is required for anti-HIV activity. Using purified calf adenosine deaminase, DAPD has a K(m) of 11 microM and a kcat of 0.25 s-1. In CEM cells exposed to DXG, the compound is readily converted to the 5O- mono-, di-, and triphosphate derivatives. DAPD, on the other hand, is not phosphorylated in CEM cells, but is first deaminated to DXG and then converted to the nucleotide forms of DXG. DXG 5O-triphosphate is a potent inhibitor of the HIV-RT giving a Ki of 0.019 +/- 0.002 microM. In contrast, the 5O-triphosphate of DAPD is a weak inhibitor of the HIV-RT with a Ki of 250 +/- 25 microM. Against the human alpha-DNA polymerase both DXG- and DAPD-5O-triphosphate show weak inhibition with Ki values of 78 +/- 17 microM and 1200 +/- 100 microM, respectively. CONCLUSIONS: DAPD, a novel prodrug that is converted to DXG, shows potent and specific in vitro anti-HIV activity with little or no cytotoxicity. DAPD is currently being developed for the treatment of disease due to HIV and hepatitis B virus.

Publication Types:

• Meeting Abstracts

Keywords:

• Acquired Immunodeficiency Syndrome
• Dioxolanes
• Guanosine
• HIV Infections
• HIV Seropositivity
• HIV-1
• Humans
• In Vitro
• Prodrugs
• dioxolane guanosine
• formal glycol
• reverse transcriptase, Human immunodeficiency virus 1

Other ID:

• 98387973

UI: 102227386

From Meeting Abstracts