Inhibition of HIV reverse transcriptase by 2′,3′-dideoxynucleoside triphosphates

Chen, Ming S.; Oshana, Scott

doi:10.1016/0006-2952(87)90685-x

Cited by 45 publications

(14 citation statements)

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“…The variations in structure-activity relationships observed among the various studies may result from a variety of factors. First, AZT and the dideoxynucleosides require phosphorylation for activity (1,7,13,15); it is possible that some of these compounds may not be good substrates for phosphorylation in E. coli. Second, metabolic inactivation of nucleosides such as ddA and ddC may occur because of deamination (7,8,30,39).…”

Section: Resultsmentioning

confidence: 99%

“…First, AZT and the dideoxynucleosides require phosphorylation for activity (1,7,13,15); it is possible that some of these compounds may not be good substrates for phosphorylation in E. coli. Second, metabolic inactivation of nucleosides such as ddA and ddC may occur because of deamination (7,8,30,39). Third, there appear to be differences in the abilities of microbial and mammalian DNA polymerases to incorporate dideoxynucleoside triphosphates into growing DNA chains (1,6,18,38); there also may be differences in the proofreading functions of various DNA polymerases or VOL.…”

Section: Resultsmentioning

confidence: 99%

“…In the literature, the mechanism by which AZT and dideoxynucleosides (as their 5'-triphosphates) inhibit HIV is reported to be inhibition of retroviral reverse transcriptase (7,15,25,28,36,41). Reverse transcriptase inhibition has become a commonly used biological endpoint for the discovery of new anti-HIV agents (7,25,36,41).…”

Section: Resultsmentioning

confidence: 99%

“…Reverse transcriptase inhibition has become a commonly used biological endpoint for the discovery of new anti-HIV agents (7,25,36,41). However, some studies have shown that the viral reverse transcriptase can incorporate AZT-5'-triphosphate into viral DNA, leading to DNA chain termination (2,14,26,27).…”

Section: Resultsmentioning

confidence: 99%

“…A proposed mechanism of action of these agents is the inhibition of human immunodeficiency virus (HIV) reverse transcriptase after nucleoside phosphorylation to their respective 5'-triphosphates (7,15,18,25,28,36,41). These agents have other biological activities, notably, an ability to terminate DNA chain elongation (1, 38, 39).…”

mentioning

confidence: 99%

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Induction of the SOS response in Escherichia coli by azidothymidine and dideoxynucleosides

Mamber

Brookshire

Forenza

1990

Antimicrob Agents Chemother

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A number of nucleosides with anti-human immunodeficiency virus (HIV) activity were evaluated in two colorimetric (j-galactosidase) assays for induction of the SOS response in Escherichia coli. 3'-Azido-3'-deoxythymidine (azidothymidine; AZT), 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyguanosine (ddG), and 2',3'-dideoxyinosine (ddl) induced cel filamentation (sulA) and prophage lambda in well-agar diffusion and liquid microsuspension assays. AZT was approximately 100 times more potent than the dideoxypurine nucleosides, inducing sulA at <100 ng/ml. 2',3'-Dideoxythymidine (ddT) and 2',3'-dideoxy-2',3'-didehydrothymidine (D4T) induced sulA at 100 to 1,000 jg/ml, while 2',3'-dideoxycytidine (ddC) weakly induced prophage lambda. Activity relationships thus were AZT > ddA 2 ddl 2 ddG > ddT = D4T > ddC. ddA and ddl had equivalent activities in agar diffusion assays, but different activity profiles were observed in liquid microsuspension assays. The differences may be related to drug metabolism. AZT and ddA showed marginal effects in a DNA repair (preferential toxicity) assay in which E. coli WP2 and CM871 uvrA recA lexA were used. Furthermore, none of the agents was able to preferentially inhibit BaciUus subtilis M45 recA relative to wild-type strain H17. These data suggest that AZT and the dideoxynucleosides do not cause DNA lesions that are repairable by excision repair and/or error-free postreplication repair processes. Rather, the SOS response appears to be induced by DNA chain termination leading to the inhibition of DNA replication. Bacterial assays for induction of the SOS response may be useful as simple, rapid prescreens for the discovery of new anti-HIV agents. Moreover, such assays may provide an additional parameter in the evaluation of agents with demonstrated activity against HIV and other retroviruses.3'-Azido-3'-deoxythymidine (azidothymidine; AZT) and dideoxynucleosides such as 2',3'-dideoxyadenosine (ddA) and 2',3'-dideoxyinosine (ddI) have potential value in the chemotherapy of patients with acquired immunodeficiency syndrome (3,4,26,28,47). A proposed mechanism of action of these agents is the inhibition of human immunodeficiency virus (HIV) reverse transcriptase after nucleoside phosphorylation to their respective 5'-triphosphates (7,15,18,25,28,36,41). These agents have other biological activities, notably, an ability to terminate DNA chain elongation (1, 38, 39). DNA chain termination may play a role in the effects of these agents on HIV (2,4,14,26,27,36). Moreover, DNA chain termination is the mechanism postulated to explain the bactericidal effects of ddA and AZT against Escherichia coli and other members of the family Enterobacteriaceae (6,13). In 1972, Geissler et al. (16) reported that ddA induces prophage lambda in E. coli. Elwell et al. (13) noted that AZT causes filamentation of E. coli cells. These results suggest that AZT and the dideoxynucleosides are capable of inducing the SOS response (21, 34, 42-44), either by causing DNA damage or by inhibiting DNA replication. However, in the Sa...

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