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

Nat Commun. 2021 Jul 7;12(1):4181. doi: 10.1038/s41467-021-24509-7.

Abstract

Nucleobase and nucleoside analogs (NNA) are widely used as anti-viral and anti-cancer agents, and NNA phosphorylation is essential for the activity of this class of drugs. Recently, diphosphatase NUDT15 was linked to thiopurine metabolism with NUDT15 polymorphism associated with drug toxicity in patients. Profiling NNA drugs, we identify acyclovir (ACV) and ganciclovir (GCV) as two new NNAs metabolized by NUDT15. NUDT15 hydrolyzes ACV and GCV triphosphate metabolites, reducing their effects against cytomegalovirus (CMV) in vitro. Loss of NUDT15 potentiates cytotoxicity of ACV and GCV in host cells. In hematopoietic stem cell transplant patients, the risk of CMV viremia following ACV prophylaxis is associated with NUDT15 genotype (P = 0.015). Donor NUDT15 deficiency is linked to graft failure in patients receiving CMV-seropositive stem cells (P = 0.047). In conclusion, NUDT15 is an important metabolizing enzyme for ACV and GCV, and NUDT15 variation contributes to inter-patient variability in their therapeutic effects.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyclovir / pharmacology*
  • Acyclovir / therapeutic use
  • Adolescent
  • Adult
  • Aged
  • Animals
  • Antibiotic Prophylaxis
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Biological Variation, Population / genetics
  • Cell Line
  • Child
  • Child, Preschool
  • Crystallography, X-Ray
  • Cytomegalovirus / drug effects
  • Cytomegalovirus / genetics
  • Cytomegalovirus / isolation & purification
  • Cytomegalovirus Infections / diagnosis
  • Cytomegalovirus Infections / etiology
  • Cytomegalovirus Infections / prevention & control*
  • Cytomegalovirus Infections / virology
  • DNA, Viral / blood
  • DNA, Viral / isolation & purification
  • Disease Models, Animal
  • Drug Resistance, Viral
  • Female
  • Ganciclovir / analogs & derivatives*
  • Ganciclovir / pharmacology
  • Ganciclovir / therapeutic use
  • Hematopoietic Stem Cell Transplantation / adverse effects
  • Host Microbial Interactions / genetics
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Middle Aged
  • Muromegalovirus / isolation & purification
  • Muromegalovirus / pathogenicity
  • Pharmacogenomic Variants
  • Polymorphism, Single Nucleotide
  • Pyrophosphatases / genetics*
  • Pyrophosphatases / metabolism
  • Pyrophosphatases / ultrastructure
  • Treatment Outcome
  • Young Adult

Substances

  • Antiviral Agents
  • DNA, Viral
  • ganciclovir triphosphate
  • NUDT15 protein, human
  • Pyrophosphatases
  • Ganciclovir
  • Acyclovir