Strigolactone Analogs Are Promising Antiviral Agents for the Treatment of Human Cytomegalovirus Infection.

Matteo Biolatti,Cristina Prandi,Marco Blangetti,Giulia D’Arrigo,Paolo Ravanini,Francesca Spyrakis,Marco De Andrea,Paola Cappello,Valentina Dell’Oste,Camilla Albano,Santo Landolfo

doi:10.3390/microorganisms8050703

Abstract

The human cytomegalovirus (HCMV) is a widespread pathogen and is associated with severe diseases in immunocompromised individuals. Moreover, HCMV infection is the most frequent cause of congenital malformation in developed countries. Although nucleoside analogs have been successfully employed against HCMV, their use is hampered by the occurrence of serious side effects. There is thus an urgent clinical need for less toxic, but highly effective, antiviral drugs. Strigolactones (SLs) are a novel class of plant hormones with a multifaceted activity. While their role in plant-related fields has been extensively explored, their effects on human cells and their potential applications in medicine are far from being fully exploited. In particular, their antiviral activity has never been investigated. In the present study, a panel of SL analogs has been assessed for antiviral activity against HCMV. We demonstrate that TH-EGO and EDOT-EGO significantly inhibit HCMV replication in vitro, impairing late protein expression. Moreover, we show that the SL-dependent induction of apoptosis in HCMV-infected cells is a contributing mechanism to SL antiviral properties. Overall, our results indicate that SLs may be a promising alternative to nucleoside analogs for the treatment of HCMV infections.

Highlights

Human cytomegalovirus (HCMV), which is part of the Betaherpesvirinae subfamily, is one of the most significant opportunistic human pathogens
In order to identify novel compounds that are capable of inhibiting HCMV replication in vitro, we screened a series of SL analogs, named TH-EGO, EDOT-EGO, EGO-10 and GR24, which had previously been characterized for their anti-proliferative [11,12] and anti-inflammatory activities [13,14,15]
Different concentrations of each molecule were tested, and the compounds were only considered non-toxic if they maintained at least 70% cell viability after 144 h of treatment. This parameter indicated that the cytotoxicity of the compounds shown in Figure 1A (i.e., TH-EGO, EDOT-EGO, EGO-10 and GR24) for primary hhuummaann ffoorreesskin fifibroblast (HFF) was low or undetectable at concentrations of up to 25 μM as ~90% of treated cells were viable after 144 h (Figure 1A)

Summary

Introduction

Human cytomegalovirus (HCMV), which is part of the Betaherpesvirinae subfamily, is one of the most significant opportunistic human pathogens. HCMV is the most common cause of congenital malformations in developed countries, resulting in neurodevelopmental delay, fetal and neonatal death, and most frequently sensorineural hearing loss [2,3]. Available drugs for anti-HCMV therapy are currently mainly composed of nucleoside, nucleotide and non-nucleotide inhibitors of viral DNA synthesis [4]. These agents suffer from several drawbacks, including the induction of adverse side effects, especially in the treatment of congenital infections, and the selection of single- or multi-resistant HCMV mutants [2]. There is a burning need to develop new compounds against HCMV diseases

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