Acyclovir: Discovery, mechanism of action, and selectivity

@article{Elion1993AcyclovirDM,
  title={Acyclovir: Discovery, mechanism of action, and selectivity},
  author={Gertrude Bell Elion},
  journal={Journal of Medical Virology},
  year={1993},
  volume={41}
}
  • G. Elion
  • Published 1993
  • Biology, Medicine
  • Journal of Medical Virology
The reasons for acyclovir's activity and selectivity in cells infected with HSV or VZV may be summarized as follows: 1. Activation by a HSV- or VZV-specified TK. 2. Greater sensitivity of viral DNA polymerase than of the cellular polymerases to ACV-TP. 3. Inactivation of the viral DNA polymerase, but not the cellular polymerases, by ACV-TP. 4. Chain termination of viral DNA by incorporation of ACV-MP. For the Epstein-Barr virus, which is also sensitive to acyclovir, there is no selective… 
Separation methods for acyclovir and related antiviral compounds.
TLDR
The measurements of acyclovir and penciclovir have been presented but in the future other related drugs will probably be available using CE methods, as this methodology is characterised by good specificity and accuracy and it is particularly useful when metabolites need to be monitored.
Association between sensitivity of viral thymidine kinase-associated acyclovir-resistant herpes simplex virus type 1 and virulence
TLDR
A statistically significant correlation between the virulence and susceptibility to ACV among ACVr HSV-1 clones was demonstrated and it was demonstrated that the higher the ACV-sensitvity, the the higherThe virulence among the ACvr clones.
Substrate specificity and molecular modelling of the feline herpesvirus-1 thymidine kinase
TLDR
Three-dimensional model of this enzyme was constructed based on sequence homology with two other herpesviral TKs, encoded by equine herpesvirus-4 (EHV-4) and herpes simplex-1 (HSV-1), and identified two residues as being critical for the differential ability of this enzymes to phosphorylate nucleoside analogues.
Resistance of Herpes Simplex Viruses to Nucleoside Analogues: Mechanisms, Prevalence, and Management
TLDR
The gold standard phenotypic method for evaluating the susceptibility of HSV isolates to antiviral drugs is the plaque reduction assay and there is a need to develop new antiherpetic compounds with different mechanisms of action.
Synergistic inhibition of herpesvirus replication by docosanol and antiviral nucleoside analogs.
TLDR
The ability of docosanol treatment to increase the antiviral activities of nucleoside analog antiviral drugs, coupled with a lack of toxic interactions, translates to substantial improvements in drug selectivity ratios.
Characterization of the DNA polymerase gene of varicella-zoster viruses resistant to acyclovir.
The nucleotide changes of the DNA polymerase gene and the susceptibility of acyclovir (ACV)-resistant varicella-zoster virus (VZV) mutants to anti-herpetic drugs were determined and compared to those
Susceptibilities of Herpes Simplex Viruses to Penciclovir and Acyclovir in Eight Cell Lines
TLDR
Among the transformed cell lines producing well-defined plaques, A549 cells provided the best concordance between IC50s for the two HSV types and two antiherpes drugs.
MODERN ETHIOTROPIC CHEMOTHERAPY OF HERPESVIRUS INFECTIONS: ADVANCES, NEW TRENDS AND PERSPECTIVES. ALPHAHERPESVIRUSES (PART II)
A key role in the treatment of herpesviral infections is played by modified nucleosides and their predecessors - acyclovir, its L-valine ester (valaciclovir) and famciclovir (prodrug of penciclovir).
Penciclovir is a potent inhibitor of feline herpesvirus-1 with susceptibility determined at the level of virus-encoded thymidine kinase.
TLDR
Data provided direct evidence that PCV is a potent selective inhibitor of FHV-1 and that the virus-encoded TK is an important determinant of the virus susceptibility to nucleoside analogues.
Herpes simplex virus resistance to antiviral drugs.
  • F. Morfin, D. Thouvenot
  • Biology, Medicine
    Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology
  • 2003
Herpes simplex virus (HSV) infections are efficiently treated with antiviral drugs such as acyclovir (ACV). However, resistance has been reported, mainly among immunocompromised patients (prevalence
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References

SHOWING 1-10 OF 18 REFERENCES
Mechanism of action and selectivity of acyclovir.
  • G. Elion
  • Medicine
    The American journal of medicine
  • 1982
Acyclovir, an acrylic purine nucleoside analog, is a highly potent inhibitor of herpes simplex virus (HSV), types 1 and 2, and varicella zoster virus, and has extremely low toxicity for the normal
Acyclovir inhibition of Epstein-Barr virus replication.
TLDR
The results suggest that a competitive mechanism is the major mode of acyclovir inhibition of EBV replication, and the virus-producing cell line P3HRF-1 consistently shows reduced viral genome numbers and viral capsid antigen on prolonged exposure to acyClovir.
In vitro susceptibility of varicella-zoster virus to acyclovir
TLDR
Analysis of the metabolism of acyclovir in varicella-zoster virus-infected WI-38 cells revealed that, as with herpes simplex virus types 1 and 2, the formation of the triphosphate forms of the drug is specific to viral infection.
Acyclovir-resistant mutants of herpes simplex virus type 1 express altered DNA polymerase or reduced acyclovir phosphorylating activities
The biochemical properties of four acyclovir-resistant mutants are described. Two of these mutants, PAAr5 and BWr, specified nucleotidyl transferase (DNA polymerase) activities which were less
Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine.
TLDR
Acycloguanosine triphosphate inhibits herpes simplex virus DNA polymerase (DNA nucleotidyltransferase) 10-30 times more effectively than cellular (HeLa S3) DNA polymerases, contributing to the drug's selectivity.
Acyclovir transport into human erythrocytes.
TLDR
Results indicate that ACV enters human erythrocytes chiefly via the same nucleobase carrier that transports adenine, guanine, and hypoxanthine.
Herpes simplex virus type 1 DNA polymerase. Mechanism of inhibition by acyclovir triphosphate.
TLDR
Studies indicated that potent, reversible inhibition by ACVTP and the next required deoxynucleoside 5'-triphosphate also occurred when poly(dC)-oligo(dG) or activated calf thymus DNA were used as the template-primer, and the reversibility of the dead-end complex was demonstrated.
Acyclovir triphosphate is a suicide inactivator of the herpes simplex virus DNA polymerase.
TLDR
Data indicate that ACVTP functions as a suicide inactivator of the herpes simplex virus type 1 DNA polymerase, and is only a weak reversible inhibitor ofDNA polymerase alpha.
Inhibition of cellular alpha and virally induced deoxyribonucleic acid polymerases by the triphosphate of acyclovir
TLDR
Human cytomegalovirus and the H29R strain of herpes simplex virus type 1, however, were found to be relatively insusceptible to acyclovir, even though their induced DNA polymerases were inhibited by low concentrations of acyClo-GTP.
Thymidine kinase from herpes simplex virus phosphorylates the new antiviral compound, 9-(2-hydroxyethoxymethyl)guanine.
TLDR
Low acyclo-Guo phosphorylating levels in cells infected with either of two herpes simplex virus mutants or with vaccinia virus correlated with low effectiveness of the compound against the virus in tissue culture.
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