Design and Synthesis of 2‘,3‘-Dideoxy- 2‘,3‘-didehydro-β-<scp>l</scp>-cytidine (β-<scp>l</scp>-d4C) and 2‘,3‘-Dideoxy-2‘,3‘-didehydro-β-<scp>l</scp>-5- fluorocytidine (β-<scp>l</scp>-Fd4C), Two Exceptionally Potent Inhibitors of Human Hepatitis B Virus (HBV) and Potent Inhibitors of Human Immunodeficiency Virus (HIV) in Vitro

Lin, Tao; Luo, Mei-Zhen; Liu, Mao-Chin; Zhu, Yangyang; Gullen, Elizabeth A.; Dutschman, Ginger E.; Cheng, Yung‐Chi

doi:10.1021/jm950836q

Cited by 124 publications

(66 citation statements)

References 16 publications

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“…␤-L-Fd4C was synthesized in the Department of Pharmacology and the Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Conn., as described by Lin et al (28). 3TC was provided by VION Pharmaceuticals.…”

Section: Methodsmentioning

confidence: 99%

“…With this aim, new antiviral compounds are usually assessed in experimental models of hepadnavirus replication (30), including in vitro hepatocyte culture (10,19,31) Recently, the novel cytidine analog ␤-L-2Ј,3Ј-dideoxy-2Ј,3Ј-didehydro-5-fluorocytidine (␤-L-Fd4C) was synthesized, and it was shown to inhibit HBV replication in the 2.2.1.5 cell line without inducing significant mitochondrial DNA toxicity in CEM cells (4,28,39,45 …”

mentioning

confidence: 99%

“…Recently, the novel cytidine analog ␤-L-2Ј,3Ј-dideoxy-2Ј,3Ј-didehydro-5-fluorocytidine (␤-L-Fd4C) was synthesized, and it was shown to inhibit HBV replication in the 2.2.1.5 cell line without inducing significant mitochondrial DNA toxicity in CEM cells (4,28,39,45). Evaluation in the DHBV infection model showed that ␤-L-Fd4C is a more potent inhibitor of the DHBV reverse transcriptase than 3TC and other cytidine analog triphosphates and inhibits viral DNA synthesis in primary duck hepatocyte cultures.…”

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confidence: 99%

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Antiviral Activity of β- l -2′,3′-Dideoxy-2′,3′-Didehydro-5-Fluorocytidine in Woodchucks Chronically Infected with Woodchuck Hepatitis Virus

Guerhier

Pichoud

Jamard

et al. 2001

Antimicrob Agents Chemother

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The L-nucleoside analog ␤-L-2,3-dideoxy-2,3-didehydro-5-fluorocytidine (␤-L-Fd4C) was first shown to exhibit potent activity against hepatitis B virus (HBV) in tissue culture and then to significantly inhibit viral spread during acute infection in the duck HBV model (F. Le Guerhier et al., Antimicrob. Agents Chemother. 44:111-122, 2000). We have therefore examined its antiviral activity in a mammalian model of chronic HBV infection, the woodchuck chronically infected with woodchuck hepatitis virus (WHV). Side-by-side comparison of ␤-L-Fd4C and lamivudine administered intraperitoneally during short-term and long-term protocols demonstrated a more profound inhibition of viremia in ␤-L-Fd4C-treated groups. Moreover, ␤-L-Fd4C induced a marked inhibition of intrahepatic viral DNA synthesis compared with that induced by lamivudine. Nevertheless, covalently closed circular (CCC) DNA persistence explained the lack of clearance of infected hepatocytes expressing viral antigens and the relapse of WHV replication after drug withdrawal. Liver histology showed a decrease in the inflammatory activity of chronic hepatitis in woodchucks receiving ␤-L-Fd4C. An electron microscopy study showed the absence of ultrastructural changes of hepatic mitochondria, biliary canaliculi, and bile ducts. However, a loss of weight was observed in all animals, whatever the treatment, as was a transient skin pigmentation in all woodchucks during ␤-L-Fd4C treatment. There was no evidence that lamivudine or ␤-L-Fd4C could prevent the development of hepatocellular carcinoma with the protocols used. These results indicate that ␤-L-Fd4C exhibits a more potent antiviral effect than lamivudine in the WHV model but was not able to eradicate CCC DNA and infected cells from the liver at the dosage and with the protocol used.Chronic hepatitis B virus (HBV) infection remains a major public health problem worldwide due to its natural history, which includes the progression to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (25). The recent approval of lamivudine [␤-L(Ϫ)-2Ј,3Ј-dideoxy-3Ј-thiacytidine, also called 3TC or L(Ϫ)SddC] has opened new perspectives for the therapy of chronic hepatitis B. In all clinical trials, 3TC was shown to be well tolerated and to be a very potent inhibitor of HBV replication (7, 24). However, due to the long half-life of infected hepatocytes and the persistence of viral covalently closed circular (CCC) DNA in infected hepatocytes, long-term treatment is required to control or eradicate viral infection (29, 34). The spontaneous HBV genome variability gives rise to a progressive selection of drug-resistant variants in 16 to 43% of the patients after 1 year of therapy (7, 24). These mutations located in the conserved B and C domains of the HBV reverse transcriptase confer resistance to 3TC (2, 49).Therefore, the design and evaluation of new molecules with anti-HBV activity remain major goals. With this aim, new antiviral compounds are usually assessed in experimental models of hepadnavirus replication (30), includ...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Antiviral Activity of β- l -2′,3′-Dideoxy-2′,3′-Didehydro-5-Fluorocytidine in Woodchucks Chronically Infected with Woodchuck Hepatitis Virus

Guerhier

Pichoud

Jamard

et al. 2001

Antimicrob Agents Chemother

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“…51,52.53 Cytidine itself has antiviral properties against Hepatitis B and HIV virus. 54,55 Another "hit" molecule that needs to be mentioned is Formoterol (DB00983). In a study conducted in Utrecht University, Netherlands this drug was effective against all enterovirus and rhinoviruses tested.…”

Section: Discussionmentioning

confidence: 99%

Energy Based Pharmacophore Modelling and Docking Studies for Determining Potent Inhibitor Against M2 Proton Channel of Influenza Virus

Kanagavelu¹,

Sunny²,

Balasundaram³

et al. 2018

IJPER

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M2 protein, a crucial glycoprotein present on the viral envelope of Influenza A virus plays an important role in the replication and budding of influenza A virus in the host organism. Due to its primal role in the life cycle of influenza A virus, it is targeted by many potent drugs like amantadine and rimantadine. The emergence of M2 protein mutants in the recent years has rendered these drugs ineffective. Keeping this in our minds, an investigation was performed to determine potent inhibitors of M2 protein using computational strategies like e-pharmacophore based virtual screening and molecular docking. A three dimensional pharmacophore model was generated based on the chemical features using PHASE module of Schrödinger Suite. Subsequently, molecules with same pharmacophoric features were screened from a total of 8621 molecules available in the DrugBank database using the generated pharmacophore hypothesis. This was followed by molecular docking of the screened molecules using three methodologies namely HTVS, SP and XP. Ligand filtration was also done to obtain an efficient collection of hit molecules by analysing pharmacokinetic properties by using Qikprop module. Consequently, our study ascertained nine molecules namely, DB00374, DB00770, DB05015, DB08868, DB00631, DB00983, DB01262, DB00837 and DB01048 which were found to possess anti-viral properties. It is also worth mentioning that antiviral activity of these compounds has been previously reported in recent literature.

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“…Effects of flurorine on cytidine analogue incorporation into a DNA 23-mer primer directed by a DNA or RNA 45-mer template 2′-or 3′-position of the deoxyribose ring in order to either mimic the presence of a 3′-hydroxyl or to stabilize the nucleoside (Herdewijn et al, 1987;Lee et al, 1999;Lee et al, 2002). Modifying the 5-or 2′-position with a fluorine can reduce toxicity (Schinazi et al, 1992b;Tsai et al, 1994) and increase antiviral potency (Schinazi et al, 1992b;Lin et al, 1994;Lin et al, 1996;Lee et al, 1999).…”

Section: Fluorine In Drug Designmentioning

confidence: 99%

Probing the Mechanistic Consequences of 5-Fluorine Substitution on Cytidine Nucleotide Analogue Incorporation by HIV-1 Reverse Transcriptase

Ray

Schinazi

Murakami

et al. 2003

Antivir Chem Chemother

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β-D and β-L-enantiomers of 2′,3′-dideoxycytidine analogues are potent chain-terminators and antimetabolites for viral and cellular replication. Seemingly small modifications markedly alter their antiviral and toxicity patterns. This review discusses previously published and recently obtained data on the effects of 5- and 2′-fluorine substitution on the pre-steady state incorporation of 2′-deoxycytidine-5′-monophosphate analogues by HIV-1 reverse transcriptase (RT) in light of their biological activity. The addition of fluorine at the 5-position of the pyrimidine ring altered the kinetic parameters for all nucleotides tested. Only the 5-fluorine substitution of the clinically relevant nucleosides (-)-β-L-2′,3′-dideoxy-3′-thia-5-fluoro-cytidine (L-FTC, Emtriva™), and (+)-β-D-2′,3′-dide-hydro-2′,3′-dideoxy-5-fluorocytidine (D-D4FC, Reverset™), caused a higher overall efficiency of nucleotide incorporation during both DNA- and RNA-directed synthesis. Enhanced incorporation by RT may in part explain the potency of these nucleosides against HIV-1. In other cases, a lack of correlation between RT incorporation in enzymatic assays and antiviral activity in cell culture illustrates the importance of other cellular factors in defining antiviral potency. The substitution of fluorine at the 2′ position of the deoxyribose ring negatively affects incorporation by RT indicating the steric gate of RT can detect electrostatic perturbations. Intriguing results pertaining to drug resistance have led to a better understanding of HIV-1 RT resistance mechanisms. These insights serve as a basis for understanding the mechanism of action for nucleoside analogues and, coupled with studies on other key enzymes, may lead to the more effective use of fluorine to enhance the potency and selectivity of antiviral agents.

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Cited by 124 publications

References 16 publications

Antiviral Activity of β- l -2′,3′-Dideoxy-2′,3′-Didehydro-5-Fluorocytidine in Woodchucks Chronically Infected with Woodchuck Hepatitis Virus

Antiviral Activity of β- l -2′,3′-Dideoxy-2′,3′-Didehydro-5-Fluorocytidine in Woodchucks Chronically Infected with Woodchuck Hepatitis Virus

Energy Based Pharmacophore Modelling and Docking Studies for Determining Potent Inhibitor Against M2 Proton Channel of Influenza Virus

Probing the Mechanistic Consequences of 5-Fluorine Substitution on Cytidine Nucleotide Analogue Incorporation by HIV-1 Reverse Transcriptase

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