The Triterpenoid MOMORDIN-Ic Inhibits HCMV by Preventing the Initiation of Gene Expression in Eukaryotic Cells

TL;DR

Mormordin Ic is a plant-derived compound that strongly inhibits HCMV by blocking gene expression and could help treat infections in immune-compromised patients.

Contribution

Mormordin Ic's novel anti-viral mechanism against HCMV, particularly its effect on RNA Pol II and viral promoters, is revealed.

Findings

Mormordin Ic inhibits both viral and host gene expression, especially highly induced genes.

It reduces RNA Pol II occupancy at a viral promoter and inhibits HCMV reactivation.

Mormordin Ic shows greater activity against the major immediate early promoter than the ip2 promoter.

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.

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