Stability of Carbovir, a Potent Inhibitor of HIV, to Phosphorolysis by Human Purine Nucleoside Phosphorylase

Marr, Clara L.P.; Penn, Charles R.

doi:10.1177/095632029200300207

Cited by 5 publications

(2 citation statements)

References 14 publications

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“…In the SAX radiochromatograms, the peak eluting near 72 min in this gradient was also seen in extracts of cells incubated with CBV. The peak eluting immediately following CBV-TP in the profiles was GTP, most likely resulting from a minor guanosine-related contaminant, as observed by others (31,37,48).…”

supporting

confidence: 62%

Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89

Faletto

Miller

Garvey

et al. 1997

Antimicrob Agents Chemother

212

104

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The anabolism of 1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, a selective inhibitor of human immunodeficiency virus (HIV), was characterized in human T-lymphoblastoid CD4+ CEM cells. 1592U89 was ultimately anabolized to the triphosphate (TP) of the guanine analog (-)-carbovir (CBV), a potent inhibitor of HIV reverse transcriptase. However, less than 2% of intracellular 1592U89 was converted to CBV, an amount insufficient to account for the CBV-TP levels observed. 1592U89 was anabolized to its 5'-monophosphate (MP) by the recently characterized enzyme adenosine phosphotransferase, but neither its diphosphate (DP) nor its TP was detected. The MP, DP, and TP of CBV were found in cells incubated with either 1592U89 or CBV, with CBV-TP being the major phosphorylated species. We confirmed that CBV is phosphorylated by 5'-nucleotidase and that mycophenolic acid increased the formation of CBV-TP from CBV 75-fold. However, mycophenolic acid did not stimulate 1592U89 anabolism to CBV-TP. The adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) did not inhibit CBV-TP formation from CBV or 1592U89, whereas the adenylate deaminase inhibitor 2'-deoxycoformycin selectively inhibited 1592U89 anabolism to CBV-TP and reversed the antiviral activity of 1592U89. 1592U89-MP was not a substrate for adenylate deaminase but was a substrate for a distinct cytosolic deaminase that was inhibited by 2'-deoxycoformycin-5'-MP. Thus, 1592U89 is phosphorylated by adenosine phosphotransferase to 1592U89-MP, which is converted by a novel cytosolic enzyme to CBV-MP. CBV-MP is then further phosphorylated to CBV-TP by cellular kinases. This unique activation pathway enables 1592U89 to overcome the pharmacokinetic and toxicological deficiencies of CBV while maintaining potent and selective anti-HIV activity.

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supporting

confidence: 62%

Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89

Faletto

Miller

Garvey

et al. 1997

Antimicrob Agents Chemother

212

104

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“…On the other hand we didn’t observe the product formation in reaction mixtures with compounds 8–10 and E. coli PNP. This correlated with literature data, for example, the carbocyclic analogue of 2′,3′-dideoxy-2′,3′-didehydroguanosine (carbovir, a nucleoside inhibitor of HIV reverse transcriptase) also does not exhibit inhibitory properties against human PNP ( Marr and Penn, 1992 ) while many other analog of guanosine possessing the hydroxyl groups have proven to be very effective PNP inhibitors ( Morris and Montgomery, 1998 ).…”

Section: Resultssupporting

confidence: 84%

Synthesis of New 5′-Norcarbocyclic Aza/Deaza Purine Fleximers - Noncompetitive Inhibitors of E.coli Purine Nucleoside Phosphorylase

et al. 2022

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A new series of flexible 5′-norcarbocyclic aza/deaza-purine nucleoside analogs were synthesized from 6-oxybicyclo[3.1.0.]hex-2-ene and pyrazole-containing fleximer analogs of heterocyclic bases using the Trost procedure. The compounds were evaluated as potential inhibitors of E. coli purine nucleoside phosphorylase. Analog 1-3 were found to be noncompetitive inhibitors with inhibition constants of 14–24 mM. From the data obtained, it can be assumed that the new 5′-norcarbocyclic nucleoside analogs interact with the active site of the PNP like natural heterocyclic bases. But at the same time the presence of a cyclopentyl moiety with 2′ and 3′ hydroxyls is necessary for the inhibitory properties, since compounds 8–10, without those groups did not exhibit an inhibitory effect under the experimental conditions.

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Inhibition of hepatitis B virus DNA polymerase by enantiomers of penciclovir triphosphate and metabolic basis for selective inhibition of HBV replication by penciclovir

1996

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Chronic hepatitis B virus (HBV) infection has been esti-The deoxyguanosine analog penciclovir (PCV; 9-[4-mated to affect more than 300 million individuals worldwide, hydroxy-3-hydroxymethyl-but-1-yl]guanine), has shown and those affected are unable to benefit from recently develpotent antiviral activity against herpes viruses and hepoped hepatitis B surface antigen-containing vaccines. 1 Atadnaviruses. Efficacy against chronic hepatitis B virus tempts to control chronic HBV disease using antiviral chemo-(HBV) infection has been demonstrated in an animal therapy have, until recently, been relatively unsuccessful. 2,3model and in recent clinical trials of famciclovir, the oral Although early attempts to treat HBV infection with nucleoform of PCV. The antiviral activity of PCV is believed side analogs were often compromised by associated toxicity, 2,3 to be dependent on the intracellular formation of PCVthe discovery that the replication of hepadnaviral genomes triphosphate (PCV-TP) which is presumed to inhibit involves an obligatory reverse transcription step 4,5 has stimu-HBV replication by interfering with viral DNA polymerase activity. The (S)-enantiomer is preferentially formed lated renewed interest in this field. In particular, the many in herpes virus-infected cells, and is the more active nucleoside analogs which have been identified as inhibitors against the herpes simplex virus; however, little is of the human immunodeficiency virus reverse transcriptase, known about the biochemical mechanisms of PCV phos-seem to be generally regarded as potential anti-HBV phorylation or of interference with viral replication in agents.2,3 However, it is becoming increasingly clear that HBV-infected cells. Here, we report that in contrast with there are other HBV-specific enzymatic processes besides reherpes simplex virus, the (R)-enantiomer of PCV-TP is verse transcription which are potential targets for nucleoside a more potent inhibitor of HBV DNA polymerase-reverse analogs. 6,7 transcriptase (pol-RT) in vitro than the (S)-enantiomer.Compound screening using a variety of systems including In assays for HBV DNA pol-RT activity, in which purified cell-free enzyme assays, cell culture, and live animal models viral core particles were the enzyme source, the IC 50 s suggest that apart from (-)-b-L-2,3-dideoxy-3-thiacytidine for (R)-and (S)-enantiomers of PCV-TP were 2.5 mmol/L (lamivudine) and structurally related deoxycytidine anaand 11 mmol/L, respectively. The estimated K i s for (R)-logs, 3,8,9 the most efficacious anti-HBV agents identified to and (S)-PCV-TP were É0.03 mmol/L and É.04 mmol/L, date are deoxyguanosine (GdR) analogs.2,3 Members of the respectively, about 3-fold lower than the K m for deoxy-latter group with proven anti-HBV activity include acyclovir guanosine triphosphate (dGTP) in the same system. In (ACV), 10 dideoxyguanosine, 11,12 ganciclovir (GCV), 13-17 penaddition, we report that PCV metabolism is similar in ciclovir (PCV), [18][19][20][21][22] and the carbocyclic analog of 2-deoxyguaboth control ...

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Stability of Carbovir, a Potent Inhibitor of HIV, to Phosphorolysis by Human Purine Nucleoside Phosphorylase

Cited by 5 publications

References 14 publications

Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89

Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89

Synthesis of New 5′-Norcarbocyclic Aza/Deaza Purine Fleximers - Noncompetitive Inhibitors of E.coli Purine Nucleoside Phosphorylase

Inhibition of hepatitis B virus DNA polymerase by enantiomers of penciclovir triphosphate and metabolic basis for selective inhibition of HBV replication by penciclovir

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