NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir.
Nat Commun
; 12(1): 4181, 2021 07 07.
Article
em En
| MEDLINE
| ID: mdl-34234136
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antivirais
/
Pirofosfatases
/
Aciclovir
/
Ganciclovir
/
Infecções por Citomegalovirus
Tipo de estudo:
Diagnostic_studies
/
Etiology_studies
/
Prognostic_studies
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article