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NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir

Rina Nishii1, Takanori Mizuno2, Daniel Rehling3

  • 1Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

Nature Communications
|July 8, 2021
PubMed

Insights

The enzyme NUDT15 metabolizes antiviral drugs acyclovir (ACV) and ganciclovir (GCV), affecting their efficacy. NUDT15 genetic variations influence patient responses and transplant outcomes.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Genetics

Background:

  • Nucleobase and nucleoside analogs (NNAs) are crucial antiviral and anticancer drugs.
  • Phosphorylation of NNAs is vital for their therapeutic activity.
  • NUDT15, a diphosphatase, is implicated in thiopurine metabolism and drug toxicity.

Purpose of the Study:

  • To investigate the role of NUDT15 in the metabolism of acyclovir (ACV) and ganciclovir (GCV).
  • To determine the impact of NUDT15 activity on the efficacy and toxicity of ACV and GCV.
  • To explore the association between NUDT15 genotype and patient outcomes in cytomegalovirus (CMV) infections and hematopoietic stem cell transplantation.

Main Methods:

  • Profiling of NNA drugs to identify NUDT15 substrates.
  • In vitro enzymatic assays to measure NUDT15 hydrolysis of ACV and GCV triphosphate metabolites.
  • Analysis of NUDT15 genotype in hematopoietic stem cell transplant patients.
  • Correlation of NUDT15 genotype with CMV viremia and graft failure.

Main Results:

  • Acyclovir (ACV) and ganciclovir (GCV) were identified as novel NNA substrates for NUDT15.
  • NUDT15 efficiently hydrolyzes the triphosphate metabolites of ACV and GCV, reducing their antiviral activity against CMV in vitro.
  • Loss of NUDT15 function potentiates the cytotoxicity of ACV and GCV in host cells.
  • NUDT15 genotype was significantly associated with the risk of CMV viremia in patients receiving ACV prophylaxis post-transplant (P=0.015).
  • Donor NUDT15 deficiency correlated with increased graft failure in recipients of CMV-seropositive stem cells (P=0.047).

Conclusions:

  • NUDT15 is a key enzyme in the metabolism of ACV and GCV.
  • NUDT15 genetic variations contribute to inter-patient variability in the therapeutic effects and toxicity of ACV and GCV.
  • NUDT15 genotype is a predictive biomarker for CMV infection risk and transplant outcomes.

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