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

Autor:	Zhang SM; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Box 1031, 17165 Stockholm, Sweden., Rehling D; Department of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden., Jemth AS; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Box 1031, 17165 Stockholm, Sweden., Throup A; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Box 1031, 17165 Stockholm, Sweden; Sygnature Discovery Limited, BioCity, Pennyfoot Street, Nottingham NG1 1GR, UK., Landázuri N; Microbial Pathogenesis Unit, Department of Medicine, Karolinska Institutet, 17164 Stockholm, Sweden; DIS Stockholm, Melodislingan 21, 11551 Stockholm, Sweden., Almlöf I; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Box 1031, 17165 Stockholm, Sweden., Göttmann M; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Box 1031, 17165 Stockholm, Sweden; German Cancer Research Center (DKFZ), Division of Brain Tumor Translational Targets, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany., Valerie NCK; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Box 1031, 17165 Stockholm, Sweden; Science for Life Laboratory, Division of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, 14152 Huddinge, Sweden., Borhade SR; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Box 1031, 17165 Stockholm, Sweden; Red Glead Discovery AB, Scheelevägen 2, 22363 Lund, Sweden., Wakchaure P; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Box 1031, 17165 Stockholm, Sweden; Recipharm OT Chemistry AB, Virdings Alle 16, 75450 Uppsala, Sweden., Page BDG; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Box 1031, 17165 Stockholm, Sweden; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada., Desroses M; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Box 1031, 17165 Stockholm, Sweden; Sprint Bioscience AB, Hälsovägen 7, 14157 Huddinge, Sweden., Homan EJ; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Box 1031, 17165 Stockholm, Sweden., Scobie M; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Box 1031, 17165 Stockholm, Sweden., Rudd SG; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Box 1031, 17165 Stockholm, Sweden., Berglund UW; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Box 1031, 17165 Stockholm, Sweden., Söderberg-Nauclér C; Microbial Pathogenesis Unit, Department of Medicine, Karolinska Institutet, 17164 Stockholm, Sweden; Division of Neurology, Karolinska University Hospital, 17177 Stockholm, Sweden., Stenmark P; Department of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden; Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden. Electronic address: stenmark@dbb.su.se., Helleday T; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Box 1031, 17165 Stockholm, Sweden; Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2RX, UK. Electronic address: thomas.helleday@scilifelab.se.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2021 Dec 16; Vol. 28 (12), pp. 1693-1702.e6. Date of Electronic Publication: 2021 Jun 29.
DOI:	10.1016/j.chembiol.2021.06.001
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
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