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The triterpernoid Momordin-Ic inhibits HCMV by preventing initiation of gene expression in eukaryotic cells

Bradley, Eleanor; Poole, Emma L; Reeves, Matthew B; (2024) The triterpernoid Momordin-Ic inhibits HCMV by preventing initiation of gene expression in eukaryotic cells. Pathogens , 13 (7) , Article 546. 10.3390/pathogens13070546. Green open access

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Abstract

Human cytomegalovirus (HCMV) primary infection, re-infection, and reactivation from latency cause morbidity in immune-compromised patients. Consequently, potential therapeutic strategies remain of interest for the treatment of infection. Naturally occurring triterpenoids derived from plants have been demonstrated to have anti-viral activity, although their precise mechanisms of action are not always fully understood. Here, we investigate the activity of Mormordin Ic (Mc) and demonstrate that it is potently anti-viral against HCMV. Through investigation of the mechanistic basis of this anti-viral activity, we identify that it is inhibitory to both viral and host gene expression, and to highly induced genes in particular. We go on to observe that Mc impacts on RNA Pol II activity and, specifically, reduces the occupancy of elongating RNA Pol II at a viral promoter. Next, we demonstrate that Mc is inhibitory to HCMV reactivation, and in doing so identify that it has greater activity against the canonical major immediate early promoter compared to the alternative ip2 promoter located downstream. Finally, we see evidence of RNA Pol II occupancy at the ip2 promoter in undifferentiated myeloid cells. Thus, Mc is potently anti-viral and a potential tool to probe the activity of multiple promoters considered important for controlling HCMV reactivation.

Type: Article
Title: The triterpernoid Momordin-Ic inhibits HCMV by preventing initiation of gene expression in eukaryotic cells
Open access status: An open access version is available from UCL Discovery
DOI: 10.3390/pathogens13070546
Publisher version: https://doi.org/10.3390/pathogens13070546
Language: English
Additional information: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Keywords: Cytomegalovirus; latency; anti-virals; transcriptional regulation
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery-pp.ucl.ac.uk/id/eprint/10193841
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