Mechanism of disproportionate antiviral activity of 2',3'-dideoxynucleoside analogs and their classification (Meeting abstract).

Important note: Information in this article was accurate in 1994. The state of the art may have changed since the publication date.

Mechanism of disproportionate antiviral activity of 2',3'-dideoxynucleoside analogs and their classification (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 35:A1841 1994. Unique Identifier : AIDSLINE ICDB/94603527
Gao WY; Agbaria R; Driscoll JS; Mitsuya H; NCI, Bethesda, MD 20892

Abstract: The mechanism of disproportionate anti-HIV-1 activity of 2',3'-dideoxynucleoside (ddN) in resting and activated target cells was studied. The in vitro activity of various ddNs against human immunodeficiency type 1 (HIV-1) profoundly differed from each other. The divergent antiviral activity was associated with different anabolic phosphorylation of each ddN analog and the counterpart dN. Dideoxynucleosides suppressed the counterpart dNTP formation in target cells, which was dependent on the activation state of the cells and individual ddN. The comparative order of the reduction was ddC much greater than d4T, 3TC, ddI, and ddG greater than AZT greater than F-ara-ddA. Based on the phosphorylation profiles, ddN analogs can be classified into two groups depending on the activation state of a target cell: (1) Cell activation-dependent ddNs such as AZT and 2',3'-didehydro-2',3'-dideoxythymidine (d4T) that are preferentially phosphorylated, yielding higher ratios of ddNTP/dNTP, and exert more potent anti-HIV activity in activated cells than in resting cells; and (2) Cell activation-independent ddNs including 2',3'-dideoxyinosine (ddI), 2',3'-dideoxyadenosine (ddA), 2'-fluoro 2',3'-dideoxyadenine-arabinofuranoside (F-ara-ddA), 2',3'-dideoxyguanosine (ddG), 2',3'-dideoxycytidine (ddc), and 3'-thia-2',3'-dideoxycytidine (3TC) that achieve higher ratios of ddNTP/dNTP and exert more potent activity against the virus in resting cells. These results may provide a basis for the explanation of the divergent degrees of antiretroviral activity of ddN analogs observed when tested in tissue culture and when administered to patients with HIV-1 infection.

Keywords: Antiviral Agents/CLASSIFICATION/*TOXICITY Cells/DRUG EFFECTS/PHYSIOLOGY Cells, Cultured Comparative Study Dideoxynucleosides/CLASSIFICATION/*TOXICITY Human HIV-1/*DRUG EFFECTS/GROWTH & DEVELOPMENT Structure-Activity Relationship ABSTRACT
941230
M94C4327

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