1995
DOI: 10.1177/095632029500600403
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Kinetic Interaction of the Diphosphates of 9-(2-phosphonylmethoxyethyl)adenine and Other anti-HIV Active Purine Congeners with HIV Reverse Transcriptase and Human DNA Polymerases α, β and γ

Abstract: SummaryThe inhibitory effects of the diphosphates of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and its analogues on HIV reverse transcriptase and human DNA polymerases a,~, and y have been studied. The analogues investigated are the diphosphates of 9-(2-phosphonylmethoxypropyl)adenine (PMPApp), 9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine (PMPDAPpp), and (2R,5R)-9-[2,5-dihydro-5-(phosphonyl methoxy)-2-furanyl]adenine (D4APpp). These four compounds are much more inhibitory to HIV reverse transcriptase when … Show more

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Cited by 73 publications
(57 citation statements)
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“…One of the proposed mechanisms by which NRTIs interfere with mitochondrial functions is the depletion of mtDNA due to the inhibition of DNA pol ␥ by NRTI triphosphates (22,23). Some NRTI triphosphates such as ddCTP inhibit DNA pol ␥ and HIV type 1(HIV-1) reverse transcriptase with similar potencies, resulting in a narrow therapeutic window (9). Inhibition studies with DNA pol ␥ are Tenofovir-DP, the active metabolite of tenofovir and a structural analog of dATP, is a weaker inhibitor of DNA pol ␥ than most of the other NRTI triphosphates, with a K i of 60 M (9).…”
Section: Discussionmentioning
confidence: 99%
“…One of the proposed mechanisms by which NRTIs interfere with mitochondrial functions is the depletion of mtDNA due to the inhibition of DNA pol ␥ by NRTI triphosphates (22,23). Some NRTI triphosphates such as ddCTP inhibit DNA pol ␥ and HIV type 1(HIV-1) reverse transcriptase with similar potencies, resulting in a narrow therapeutic window (9). Inhibition studies with DNA pol ␥ are Tenofovir-DP, the active metabolite of tenofovir and a structural analog of dATP, is a weaker inhibitor of DNA pol ␥ than most of the other NRTI triphosphates, with a K i of 60 M (9).…”
Section: Discussionmentioning
confidence: 99%
“…As current clinical guidelines recommend combined therapy, usually including NRTI (Centers for Disease Control and Prevention, 1999), such regimens may be important to the development of mitochondrial toxicity in new tissue targets as treatment is prolonged because of the increased longevity of patients with AIDS. [The following references were cited only in Table 1: Barile et al, 1994Barile et al, , 1997Benbrik et al, 1997;Browne et al, 1993;Chen and Cheng, 1992;Cherrington et al, 1995;Corcuera et al, 1996;Cui et al, 1997;Dalakas et al, 1990;Elimadi et al, 1997. The following references were cited only in Table 1: Feldman and Anderson, 1994;Feldman et al, 1992;Hart et al, 1992;Hertzberg et al, 1992;Hobbs et al, 1992Hobbs et al, , 1995; Institute of Medicine (US) Committee to Review the Fialuridine (FIAU/FIAC) Clinical Trials, 1995;Izuta et al, 1991.…”
Section: Discussionmentioning
confidence: 99%
“…Mitochondrial structural changes and lipid accumulation in nerves of DDC-treated rabbits. Anderson et al, 1992Chen and Cheng, 1992Chen and Cheng, 1989Chen et al, 1991Cherrington et al, 1995Eriksson et al, 1995Feldman et al, 1992Feldman and Anderson, 1994Keilbaugh et al, 1993Kukhanova et al, 1995Martin et al, 1994Starnes and Cheng, 1987Tsai et al, 1994 3TC Kinetics with HeLa DNA pol-␥ Hart et al, 1992Martin et al, 1994 Carbovir K m with gapped duplex DNA Parker et al, 1991White et al, 1989 Continued…”
Section: Mtdna Dna Polymerase-␥ and Nrti Toxicitymentioning
confidence: 99%
See 1 more Smart Citation
“…This compound is an acyclic adenine derivative; its active intracellular form is PMEA diphosphate (PMEApp), a competitive inhibitor of HIV type 1 (HIV-1) RT with regard to dATP substrate (2). HIV resistance to PMEA has occurred in tissue culture protocols, and a K65R mutation has been observed to develop in HIV cultured in the presence of this drug (21a, 24).…”
mentioning
confidence: 99%