Understanding the unique mechanism of l-FMAU (Clevudine) against hepatitis B virus: molecular dynamics studies

Chong, Youhoon; Chu, Chung K.

doi:10.1016/s0960-894x(02)00747-3

Cited by 46 publications

(42 citation statements)

References 13 publications

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“…Among the synthesized nucleosides, Duridine (23), D-cytidine (24), D-5-fluorocytidine and L-cytidine (52) analogs show moderate anti-HIV activity with an EC 50 value of 6.9, 1.3, 5.8 and 14.1 μM, respectively. However, these four nucleoside analogs are also cytotoxic in PBM cells and CEM cells.…”

Section: Anti-hiv Activitymentioning

confidence: 99%

“…We synthesized D-cytidine analog at the early stages of this project, when some antiviral activity for D-cytidine analog (24 , Table 1) is observed, then we decided to explore the SAR at the 5-position of the pyrimidine ring. The addition of halogen atom at the 5-position of the pyrimidine ring has been found to alter the kinetic parameters as well as antiviral potency of the corresponding nucleoside analogues.…”

Section: Anti-hiv Activitymentioning

confidence: 99%

“…The organic layer was dried over anhydrous Na 2 SO 4 , concentrated, filtered and purified by silica get column chromatography with 10% EtOAc in hexanes to give the product 11 (1.58g, 4. 24 …”

Section: [(2r3s)-2-(tert-butyl-diphenyl-silanyloxymethyl)-thietan-3-mentioning

confidence: 99%

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Synthesis and Anti-HIV Activity of d- and l-Thietanose Nucleosides

et al. 2006

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Various D-and L-thietanose nucleosides (22-27, 33-35, 50-52, 58-60) were synthesized from D-and L-xylose. The four-membered thietane ring was efficiently synthesized by the cyclization of 1-thioacetyl-3-mesylate (4/38) under basic conditions. Condensation with various heterocyclic bases was conducted via Pummerer-type rearrangement to afford various nucleoside derivatives. Among the synthesized nucleosides, D-uridine (23), D-cytidine (24), D-5-fluorocytidine (25) and L-cytidine (52) analogs showed moderate anti-HIV activity with EC 50 of 6.9, 1.3, 5.8 and 14.1 μM, respectively. However, these four nucleoside analogs are cytotoxic in PBM and CEM cells. The other nucleosides are neither active nor cytotoxic. Interestingly, the oxetanocin A analog 33 was not active. Comparison of the minimized RTs complexed with the corresponding triphosphates of the cytidine analog 24 and the adenosine analog 33 by molecular modeling studies showed that there is no difference in the binding mode of the triphosphate of the cytidine analog 24 to the active site of HIV-1 RT from that of the triphosphate of the adenosine analog 33. Modeling studies on the initial monophosphorylation step by deoxycytidine kinase showed that the catalytic efficiency of phosphorylation through a nucleophilic attack of the 4′-hydroxyl group of thietanose on the γ-phosphate of ATP is diminished in the case of L-cytidine analog (52) due to the increased distance between the 4′-hydroxyl group and the γ-phosphate.

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Section: Anti-hiv Activitymentioning

confidence: 99%

Section: Anti-hiv Activitymentioning

confidence: 99%

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Synthesis and Anti-HIV Activity of d- and l-Thietanose Nucleosides

et al. 2006

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“…7 Chu and coworkers further utilized the same model for MD studies to explain the mechanism of action of clevudine and adefovir sensitivity and resistance. [10][11][12] Bartholomeusz et al developed another alignment of the sequence of HDP to HIV-1 RT and then also used 1RTD.pdb for building their model for HDP, and used it for mapping out the effects on the HDP model of various mutations reported in the literature. 8 Langley et al reported docking studies of entecavir using a homology model of HDP and its various mutants.…”

Section: Introductionmentioning

confidence: 99%

Computational model of hepatitis B virus DNA polymerase: Molecular dynamics and docking to understand resistant mutations

2010

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Hepatitis B virus (HBV) DNA polymerase (HDP) is a pharmacological target of intense interest. Of the seven agents approved in USA for the treatment of HBV infections, five are HDP inhibitors. However, resistance development against HDP inhibitors, such as lamivudine and adefovir, has severely hurt their efficacy to treat HBV. As a step toward understanding the mechanism of resistance development and for gaining detailed insights about the active site of the enzyme, we have built a homology model of HDP which is an advance over previously reported ones. Validation using various techniques, including PROSTAT, PROCHECK, and Verify-3D profile, proved the model to be stereochemically significant. The stability of the model was studied using a 5 ns molecular dynamics simulation. The model was found to be sufficiently stable after the initial 2.5 ns with overall root mean squared deviation (RMSD) of 4.13 Å . The homology model matched the results of experimental mutation studies of HDP reported in the literature, including those of antiviral-resistant mutations. Our model suggests the significant role of conserved residues, such as rtLys32, in binding of the inhibitors, contrary to previous studies. The model provides an explanation for the inactivity of some anti-HIV molecules which are inactive against HDP. Conformational changes which occurred in certain binding pocket amino acids helped to explain the better binding of some of the inhibitors in comparison to the substrates.

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“…It acts as a competitive inhibitor by binding to the catalytic site of HBV polymerase and inhibiting the priming of HBV DNA chain elongation. Nucleoside inhibitors, in general, interfere with viral polymerase activity through competitive inhibition and incorporation into the viral DNA strands [20] . …”

Section: Clevudine (L-fmau)mentioning

confidence: 99%

Novel approaches towards conquering hepatitis B virus infection

Wu¹

2007

WJG

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Currently approved treatments for hepatitis B virus (HBV) infection include the immunomodulatory agent, IFN-α, and nucleos(t)ide analogues. Their efficacy is limited by their side effects, as well as the induction of viral mutations that render them less potent. It is thus necessary to develop drugs that target additional viral antigens. Chemicals and biomaterials by unique methods of preventing HBV replication are currently being developed, including novel nucleosides and newly synthesized compounds such as capsid assembling and mRNA transcription inhibitors. Molecular therapies that target different stages of the HBV life cycle will aid current methods to manage chronic hepatitis B (CHB) infection. The use of immunomodulators and gene therapy are also under consideration. This report summarizes the most recent treatment possibilities for CHB infection. Emerging therapies and their potential mechanisms, efficacy, and pitfalls are discussed.

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Understanding the unique mechanism of l-FMAU (Clevudine) against hepatitis B virus: molecular dynamics studies

Cited by 46 publications

References 13 publications

Synthesis and Anti-HIV Activity of d- and l-Thietanose Nucleosides

Synthesis and Anti-HIV Activity of d- and l-Thietanose Nucleosides

Computational model of hepatitis B virus DNA polymerase: Molecular dynamics and docking to understand resistant mutations

Novel approaches towards conquering hepatitis B virus infection

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