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  • Zhang, Si MinKarolinska Institutet,Karolinska Institute (author)

NUDT15-mediated hydrolysis limits the efficacy of anti-HCMV drug ganciclovir

  • Article/chapterEnglish2021

Publisher, publication year, extent ...

  • Elsevier BV,2021
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:su-195166
  • https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-195166URI
  • https://doi.org/10.1016/j.chembiol.2021.06.001DOI
  • https://lup.lub.lu.se/record/000b115f-b385-4e21-a3f2-9ed83fbd4592URI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:148387996URI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Ganciclovir (GCV) is the first-line therapy against human cytomegalovirus (HCMV), a widespread infection that is particularly dangerous for immunodeficient individuals. Closely resembling deoxyguanosine triphosphate, the tri-phosphorylated metabolite of GCV (GCV-TP) is preferentially incorporated by the viral DNA polymerase, thereby terminating chain extension and, eventually, viral replication. However, the treatment outcome of GCV varies greatly among individuals, therefore warranting better understanding of its metabolism. Here we show that NUDT15, a Nudix hydrolase known to metabolize thiopurine triphosphates, can similarly hydrolyze GCV-TP through biochemical studies and co-crystallization of the NUDT15/GCV-TP complex. More critically, GCV efficacy was potentiated in HCMV-infected cells following NUDT15 depletion by RNAi or inhibition by an in-house-developed, nanomolar NUDT15 inhibitor, TH8321, suggesting that pharmacological targeting of NUDT15 is a possible avenue to improve existing anti-HCMV regimens. Collectively, the data further implicate NUDT15 as a broad-spectrum metabolic regulator of nucleoside analog therapeutics, such as thiopurines and GCV.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Rehling, DanielStockholm University,Stockholms universitet,Institutionen för biokemi och biofysik(Swepub:su)dare2534 (author)
  • Jemth, Ann-SofieKarolinska Institutet,Karolinska Institute (author)
  • Throup, AdamKarolinska Institute (author)
  • Landázuri, NataliaKarolinska Institute (author)
  • Almlöf, IngridKarolinska Institutet,Karolinska Institute (author)
  • Göttmann, MonaKarolinska Institute (author)
  • Valerie, Nicholas C. K.Karolinska Institutet,Karolinska Institute,Karolinska University Hospital (author)
  • Borhade, Sanjay R.Karolinska Institute (author)
  • Wakchaure, PrasadKarolinska Institute (author)
  • Page, Brent D. G.Karolinska Institute,University of Northern British Columbia (author)
  • Desroses, MatthieuKarolinska Institute (author)
  • Homan, Evert J.Karolinska Institutet,Karolinska Institute (author)
  • Scobie, MartinKarolinska Institutet,Karolinska Institute (author)
  • Rudd, Sean G.Karolinska Institutet,Karolinska Institute (author)
  • Warpman Berglund, UlrikaKarolinska Institutet,Karolinska Institute (author)
  • Söderberg-Nauclér, CeciliaKarolinska Institutet,Karolinska Institute,Karolinska University Hospital (author)
  • Stenmark, PålStockholm University,Lunds universitet,Stockholms universitet,Institutionen för biokemi och biofysik,Lund University, Sweden,Strukturell biokemi,Forskargrupper vid Lunds universitet,Structural Biochemistry,Lund University Research Groups(Swepub:lu)pa4463st (author)
  • Helleday, ThomasKarolinska Institutet,Karolinska Institute,University of Sheffield (author)
  • Karolinska InstitutetKarolinska Institute (creator_code:org_t)

Related titles

  • In:Cell Chemical Biology: Elsevier BV28:12, s. 1693-17022451-94562451-9448

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