Journal Article

DKFZ-2021-01474

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png NUDT15-mediated hydrolysis limits the efficacy of anti-HCMV drug ganciclovir.

Zhang, S. M. ; Rehling, D. ; Jemth, A.-S. ; Throup, A. ; Landázuri, N. ; Almlöf, I. ; Göttmann, M.DKFZ* ; Valerie, N. C. K. ; Borhade, S. R. ; Wakchaure, P. ; Page, B. D. G. ; Desroses, M. ; Homan, E. J. ; Scobie, M. ; Rudd, S. G. ; Berglund, U. W. ; Söderberg-Nauclér, C. ; Stenmark, P. ; Helleday, T.

2021
Elsevier Amsterdam

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Please use a persistent id in citations: doi:10.1016/j.chembiol.2021.06.001

Abstract: 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.

Keyword(s): NUDT15 ; Nudix hydrolase ; TH8321 ; antiherpes ; cytomegalovirus ; ganciclovir ; high-throughput infectivity assay ; nucleoside analog drug ; small-molecule inhibitor

Note: 2021 Dec 16;28(12):1693-1702.e6

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Contributing Institute(s):

1. B067 Translationale Zielmoleküle für Hirntumoren (B067)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2021

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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