Valacyclovir and Acyclovir Are Substrates of the Guanine Deaminase Cytosolic PSD-95 Interactor (Cypin)

Proteins: Structure, Function, and Bioinformatics, 2025 · DOI: https://doi.org/10.1002/prot.26740 · Published: January 1, 2025

Pharmacology Biochemistry

Simple Explanation

This study investigates whether valacyclovir and acyclovir, antiviral drugs, are broken down by an enzyme called cypin in the body. The researchers found that cypin does indeed deaminate (break down) these drugs, suggesting a new pathway for their metabolism. This discovery implies that cypin might affect how well purine-based drugs work, as cypin could inactivate them.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Not specified

Key Findings

1
Valacyclovir and acyclovir are deaminated by cypin, meaning cypin breaks them down.
2
Valacyclovir has a higher affinity for cypin than acyclovir, likely due to the valine motif in valacyclovir.
3
The deaminated products of valacyclovir and acyclovir can be further processed by xanthine oxidase and uricase, enzymes in the purine metabolism pathway.

Research Summary

This study demonstrates that valacyclovir and acyclovir, commonly used antiviral drugs, are substrates of the enzyme cypin, which deaminates these compounds. The research uses NADH-coupled assays, tryptophan fluorescence assays, and LC–MS to confirm the deamination of valacyclovir by cypin and the subsequent processing of its metabolites by xanthine oxidase and uricase. Molecular dynamics simulations reveal that valacyclovir binding induces conformational changes in cypin, affecting the active site structure. These findings suggest a novel metabolic pathway for these antiviral drugs and have implications for drug efficacy and inhibitor design.

Practical Implications

Drug Metabolism

The discovery of cypin's role in valacyclovir and acyclovir metabolism provides new insights into how these drugs are processed in the body, which could affect dosing strategies.

Inhibitor Design

Understanding the structural changes induced by valacyclovir binding can aid in designing more effective cypin inhibitors, potentially useful in treating conditions like neuropathic pain and hyperuricemia.

Therapeutic Efficacy

The inactivation of purine-based therapeutics by cypin suggests a need to consider this pathway when developing new drugs, to ensure they are not prematurely degraded.

Study Limitations

1
Solubility issues prevented accurate determination of Km and Vmax values for acyclovir.
2
The LC–MS assay detected deaminated valacyclovir but not the xanthine oxidase-mediated oxidation product, possibly due to the assay's short duration and low substrate abundance.
3
The potential toxicity of the deaminated valacyclovir or further oxidized variants is unknown.

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Valacyclovir and Acyclovir Are Substrates of the Guanine Deaminase Cytosolic PSD-­95 Interactor (Cypin)

Simple Explanation

Key Findings

Research Summary

Practical Implications

Drug Metabolism

Inhibitor Design

Therapeutic Efficacy

Study Limitations

Your Feedback

Was this summary helpful?

Valacyclovir and Acyclovir Are Substrates of the Guanine Deaminase Cytosolic PSD-­95 Interactor (Cypin)

Simple Explanation

Key Findings

Research Summary

Practical Implications

Drug Metabolism

Inhibitor Design

Therapeutic Efficacy

Study Limitations

Your Feedback

Was this summary helpful?

Valacyclovir and Acyclovir Are Substrates of the Guanine Deaminase Cytosolic PSD-95 Interactor (Cypin)

Valacyclovir and Acyclovir Are Substrates of the Guanine Deaminase Cytosolic PSD-95 Interactor (Cypin)