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

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.

Strigolactones, from Plants to Human Health: Achievements and Challenges

“…These results are challenging in the field of antiviral research, since, besides inhibiting the late phases of the viral cycle, apoptosis has been shown to be a novel strategy that SLs rely on to exert their inhibitory role against viral replication. These results have been confirmed by in-silico molecular docking simulations, which predict a stable protein-ligand complex between the SL analogs and the modeled structure of the putative target IE1, which is employed by HCMV to escape apoptosis [ 145 ].…”

“…Recently, our group has demonstrated, for the first time, the efficacy of a group of SL analogues as antivirals against members of the Herpesviridae family, in particular human cytomegalovirus (HCMV) [ 145 ]. HCMV is a widespread pathogen that can cause severe disease in immunocompromised individuals [ 146 ].…”

Apoptosis Disorder, a Key Pathogenesis of HCMV-Related Diseases

“…The study results provided a new way to fight immune dysfunction induced by HCMV infection [ 117 ]. In contrast, Biolatti et al demonstrated that strigolactones exert their antiviral properties by inducing the apoptosis of HCMV-infected cells [ 118 ]. Similarly, Mo et al revealed that treatment with chloroquine remarkably enhances the expression of cleaved caspase-3 in MCMV-infected retinal pigment epithelial cells and contributes to the apoptosis of infected cells [ 119 ].…”

Strigolactones: Phytohormones with Promising Biomedical Applications

“…The antiviral activity of a panel of synthetic SLS was tested against HMCV (Human Citomegalovirus) with the aim of identifying new druggable targets for anti‐HCMV therapy to be used in place of nucleoside therapy whose side effects are reported as very serious [42] . Compound 19 and 20 a (Figure 2) markedly inhibit the replication of different HCMV strains in vitro.…”

“…In particular, the authors show that an SL‐dependent trigger for apoptosis of the infected cell may be a novel strategy against HCMV infection. Finally, in silico molecular docking simulations have been used to predict the interactions between the SL analogs and the modeled structure of the putative target IE1, which is known to inhibit apoptosis [42] . Antiviral therapy that is based on molecules exerting their effects by targeting cellular proteins instead of specific viral proteins is a promising solution, as they are not associated with drug resistance.…”