Related Experiment Video

Updated: Aug 9, 2026

Analysis of Group IV Viral SSHHPS Using In Vitro and In Silico Methods
10:40

Analysis of Group IV Viral SSHHPS Using In Vitro and In Silico Methods

Published on: December 21, 2019

Mutations distal to the substrate site can affect varicella zoster virus thymidine kinase activity: implications for

Kamel El Omari1, Sandra Liekens, Louise E Bird

  • 1Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.

Molecular Pharmacology
|March 25, 2006
PubMed

Insights

Varicella zoster virus thymidine kinase (VZVTK) mutations enhance selectivity for antiviral drugs and gene therapy. Site-directed mutagenesis studies reveal key residues for improved drug design against VZV and cancer.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Virology

Background:

  • Varicella zoster virus thymidine kinase (VZVTK) activates antiherpetic drugs and is explored for cancer therapy.
  • Understanding VZVTK's structure-activity relationship is crucial for developing selective antiviral and anticancer agents.

Purpose of the Study:

  • To investigate structure-based, site-directed mutagenesis of VZVTK to improve compound selectivity.
  • To identify key residues influencing substrate activity and inhibition by nucleoside analogs.

Main Methods:

  • Construction and characterization of six VZVTK mutants (E59S, R84V, H97Y/A, Y21H/E).
  • Assays for substrate phosphorylation activity with deoxythymidine (dThd).
  • Competitive inhibition studies using bicyclic nucleoside analogs (BCNAs).

Main Results:

  • Most mutants retained significant dThd phosphorylation activity, except Y21E, which showed a 350-fold decrease.
  • Residue 97 interactions are important for BCNA inhibition, suggesting aromatic ring stacking.
  • Mutation Y21E altered BCNA binding affinity, indicating residue 21's role in BCNA selectivity and potentially explaining HSV1TK's inability to bind BCNAs.

Conclusions:

  • Distal mutations in VZVTK's active site can modulate compound selectivity.
  • These findings support the rational design of more selective VZVTK substrates for gene suicide therapy or anti-VZV drugs.

More Related Videos

Understanding the Development of Compensatory Pathways in a Mutant Malaria Parasite Harbouring Hypomorphic Allele of Plant-Like Kinases09:13

Understanding the Development of Compensatory Pathways in a Mutant Malaria Parasite Harbouring Hypomorphic Allele of Plant-Like Kinases

Published on: November 22, 2024

Related Concept Videos

Antiviral Nucleoside Inhibitors01:22

Antiviral Nucleoside Inhibitors

Antiviral Nucleoside InhibitorsAntiviral nucleoside inhibitors are structural analogs of natural nucleosides that interfere with viral DNA or RNA synthesis. These compounds selectively target viral polymerases due to their resemblance to host nucleosides, thereby disrupting viral genome replication.Mechanism of Acyclovir ActionAcyclovir is a guanosine analog with a three-carbon acyclic side chain. It selectively targets herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2),...
Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu01:29

Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu

Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
Inhibitors of Viral Protein Synthesis01:30

Inhibitors of Viral Protein Synthesis

Protein synthesis is indispensable for viral replication, as viruses lack the cellular machinery required for this process and must hijack the host's translational apparatus. In response, host cells deploy a critical innate immune defense involving interferons, specialized cytokines that play a central role in inhibiting viral propagation.Upon viral detection, infected cells release interferons that bind to receptors on adjacent uninfected cells, activating the JAK-STAT signaling pathway and...
Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase

Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
Impact of Pharmacokinetic–Pharmacodynamic Models: Regulatory Decisions01:15

Impact of Pharmacokinetic–Pharmacodynamic Models: Regulatory Decisions

PK–PD modeling has significantly influenced FDA regulatory decisions, particularly drug approval, dosage optimization, and labeling. These models integrate pharmacokinetics (PK) and pharmacodynamics (PD) to predict drug behavior and effects, aiding in optimizing dosing regimens and enhancing the probability of clinical trial success.One notable example is Nesiritide (Natrecor®), a recombinant human brain natriuretic peptide for treating acute decompensated congestive heart failure (CHF).
Effect of Hepatic Disease on Pharmacokinetics: Active Drug, Metabolite and Fraction of Metabolized Drug01:14

Effect of Hepatic Disease on Pharmacokinetics: Active Drug, Metabolite and Fraction of Metabolized Drug

In pharmacotherapy, monitoring drug concentrations is paramount, especially for drugs whose therapeutic effects hinge on both the active compound and its metabolite. Hepatic impairment profoundly influences drug potency by altering liver function. If the drug is more potent than its metabolite, impaired liver function amplifies drug activity due to elevated drug concentration levels. Conversely, if the metabolite holds greater potency, diminished liver function diminishes drug activity by...