Antiviral β-L-nucleosides specific for hepatitis B virus infection

Bryant, Martin L.; Bridges, Edward G.; Placidi, L; Faraj, Abdesslem; Loi, Anna-Giulia; Pierra, Claire; Benzaria, S.; Dukhan, David; Gosselin, Gilles; Imbach, Jean‐Louis; Hernandez, Brenda Y.; Juodawlkis, Amy; Tennant, Bud C.; Korba, Brent E.; Côté, Paul J.; Cretton-Scott, Erika; Schinazi, Raymond F.; Myers, Maureen; Sommadossi, Jean‐Pierre

doi:10.1016/b978-044450986-4/50072-2

Cited by 7 publications

(7 citation statements)

References 47 publications

(37 reference statements)

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“…Nucleoside analogue usage can be limited by drug resistance and unwanted side effects . Unfortunately, a striking 15–22% of HBV patients report moderate to severe side effects (e.g., myopathy and nephrotoxicity). , These adverse events may not be derived from mitochondrial toxicity − because assays indicate that anti-HBV nucleoside analogues are weak inhibitors of Pol γ − and/or induce relatively low mitochondrial toxicity. − Since human replicative polymerases (e.g., Pols α, δ, and ε) employ stringent mechanisms of nucleotide selection, these enzymes are unlikely to incorporate PMEA-DP, PMPA-DP, ETV-TP, L-TBV-TP, or L-3TC-TP, indicating these drugs are relatively weak inhibitors. The selection factors measured for exonuclease-deficient Pol γ , and exonuclease-deficient T7 DNA polymerase, two replicative A-family enzymes, incorporating PMPA-DP are 10,800 and 54,400, respectively, which are significantly larger than the values determined for Pol β (40), Pol λ (65), and Pol η (1,800) (Table ).…”

Section: Discussionmentioning

confidence: 99%

Presteady State Kinetic Investigation of the Incorporation of Anti-Hepatitis B Nucleotide Analogues Catalyzed by Noncanonical Human DNA Polymerases

Brown

Pack

Fowler

et al. 2011

Chem. Res. Toxicol.

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Antiviral nucleoside analogs have been developed to inhibit the enzymatic activities of the hepatitis B virus (HBV) polymerase, thereby preventing the replication and production of HBV. However, the usage of these analogs can be limited by drug toxicity because the 5′-triphosphates of these nucleoside analogs (nucleotide analogs) are potential substrates for human DNA polymerases to incorporate into host DNA. Although they are poor substrates for human replicative DNA polymerases, it remains to be established whether these nucleotide analogs are substrates for the recently discovered human X- and Y-family DNA polymerases. Using pre-steady state kinetic techniques, we have measured the substrate specificity values for human DNA polymerases β, λ, η, ι, κ, and Rev1 incorporating the active forms of the following anti-HBV nucleoside analogs approved for clinical use: adefovir, tenofovir, lamivudine, telbivudine, and entecavir. Compared to the incorporation of a natural nucleotide, most of the nucleotide analogs were incorporated less efficiently (2 to >122,000) by the six human DNA polymerases. In addition, the potential for entecavir and telbivudine, two drugs which possess a 3′-hydroxyl, to become embedded into human DNA was examined by primer extension and DNA ligation assays. These results suggested that telbivudine functions as a chain terminator while entecavir was efficiently extended by the six enzymes and was a substrate for human DNA ligase I. Our findings suggested that incorporation of anti-HBV nucleotide analogs catalyzed by human X- and Y-family polymerases may contribute to clinical toxicity.

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Section: Discussionmentioning

confidence: 99%

Presteady State Kinetic Investigation of the Incorporation of Anti-Hepatitis B Nucleotide Analogues Catalyzed by Noncanonical Human DNA Polymerases

Brown

Pack

Fowler

et al. 2011

Chem. Res. Toxicol.

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“…L-nucleosides are generally less cytotoxic compared to their D-counterparts, probably because L-analogs are often less good substrates to human cellular DNA polymerases L-3´-Fd4FC [118,122]. An example is L-FMAU, which is more potent than FMAU against HBV, at the same time less cytotoxic.…”

Section: L-nucleosidesmentioning

confidence: 97%

“…L-dC (54, valtoricitabine) and L-dT (55, Telbivudine) are in the advanced development phase for HBV treatment. Despite that the configuration of the Lnucleosides differs from that of the natural D-nucleosides, the compounds can be effectively recognized by the cellular kinases, dCK and/or TK 1 [118]. Compounds 54 and 55 are selective anti-HBV agents, and have no activity against other viruses like HIV, herpes viruses.…”

Section: L-nucleosidesmentioning

confidence: 99%

Nucleoside Analogs as Anti-HBV Agents

Zhou¹,

Littler

2006

CTMC

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Chronic hepatitis B virus (HBV) infection affects about 400 million people worldwide. The development of nucleoside analogs that inhibit HBV polymerase provides an important approach for treating HBV infection. The approval of lamivudine, adefovir and entecavir represents a cornerstone of hepatitis B therapy. However, the challenges from the resistance and the off-therapy viral rebound are still unmet, and there is a need of developing new therapeutic agents. This review will discuss the structure-activity relationship of the most significant anti-HBV nucleoside analogs and the latest development in the field.

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“…Telbivudine is a competitive inhibitor of both viral reverse transcriptase and DNA polymerase. 17 Similar to other nucleosides, telbivudine requires biotransformation to the triphosphate moiety, which is the active component and competes with naturally occurring thymidine triphosphate for viral DNA elongation. In that process, incorporation of telbivudine into the viral DNA will terminate viral DNA chain elongation ( Figure 1).…”

Section: Pharmacologymentioning

confidence: 99%

“…18 In contrast to other nucleoside analogs, telbivudine is only active against HBV, with no antiviral activity against other known human viruses. 17 In addition, telbivudine triphosphate does not inhibit human cellular polymerase alfa, beta, or gamma, which has been attributed to nucleoside-induced mitochondrial depletion and associated with development of clinically apparent neuropathy, myopathy, and lactic acidemia. 19,20 These adverse events have been attributed to nucleoside-induced mitochondrial deletion.…”

Section: Pharmacologymentioning

confidence: 99%