TY  - JOUR
AU  - Zhang, Si Min
AU  - Rehling, Daniel
AU  - Jemth, Ann-Sofie
AU  - Throup, Adam
AU  - Landázuri, Natalia
AU  - Almlöf, Ingrid
AU  - Göttmann, Mona
AU  - Valerie, Nicholas C K
AU  - Borhade, Sanjay R
AU  - Wakchaure, Prasad
AU  - Page, Brent D G
AU  - Desroses, Matthieu
AU  - Homan, Evert J
AU  - Scobie, Martin
AU  - Rudd, Sean G
AU  - Berglund, Ulrika Warpman
AU  - Söderberg-Nauclér, Cecilia
AU  - Stenmark, Pål
AU  - Helleday, Thomas
TI  - NUDT15-mediated hydrolysis limits the efficacy of anti-HCMV drug ganciclovir.
JO  - Cell chemical biology
VL  - 28
IS  - 12
SN  - 2451-9456
CY  - Amsterdam
PB  - Elsevier
M1  - DKFZ-2021-01474
SP  - 1693-1702.e6
PY  - 2021
N1  - 2021 Dec 16;28(12):1693-1702.e6
AB  - 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.
KW  - NUDT15 (Other)
KW  - Nudix hydrolase (Other)
KW  - TH8321 (Other)
KW  - antiherpes (Other)
KW  - cytomegalovirus (Other)
KW  - ganciclovir (Other)
KW  - high-throughput infectivity assay (Other)
KW  - nucleoside analog drug (Other)
KW  - small-molecule inhibitor (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:34192523
DO  - DOI:10.1016/j.chembiol.2021.06.001
UR  - https://inrepo02.dkfz.de/record/169400
ER  -