Abstract
The compound 1,2,3,4,6-penta-O-galloyl-β-d-glucose (PGG), a gallotannin present in various plants such as Rhus chinensis Mill and Paeonia suffruticosa, has a broad spectrum of antiviral effects. The present study investigated its potency against infection of mice with rabies virus (RABV). Results demonstrated that PGG strongly inhibited virus titers (50-fold), viral mRNA expression (up to 90%), and protein synthesis in vitro. Importantly, we found that PGG not only suppressed viral adsorption and entry, but also directly inactivated RABV through suppression of autophagy by mediating activation of the mTOR-dependent autophagy signaling pathway. In vivo, PGG (10 mg/kg) alleviated the clinical symptoms and reduced the mortality of infected mice by 27.3%. Collectively, our results indicate that PGG has potent anti-RABV effect, and merits further investigation as an anti-RABV drug.
Highlights
Rsbies virus (RABV) is an enveloped, single-stranded negative-sense RNA virus belonging to the genus Lyssavirus of the Rhabdoviridae family, which invades the central nervous system and causes fatal encephalitis in mammals and humans
We found that the inhibitory effect of PGG was diminished when cells were pretreated with rapamycin; the inhibitory effect of PGG was enhanced when cells were pretreated with MHY1485, which strongly supports the conclusion that mechanistic target of rapamycin (mTOR) plays a key role in PGG-induced autophagy inhibition (Figure 7a–e)
PGG is a hydrolysable gallotannin of a phenolic compound with five free hydroxyl groups of glucose and gallic acid acylation
Summary
Rsbies virus (RABV) is an enveloped, single-stranded negative-sense RNA virus belonging to the genus Lyssavirus of the Rhabdoviridae family, which invades the central nervous system and causes fatal encephalitis in mammals and humans. PGG belongs to the group of gallotannins which participates in the formation of ellagitannins It has several biological activities, including antimutagenic [10], anti-inflammatory [11], anticancer [12,13]. PGG has been reported to exert its antiviral effect by multiple mechanisms, including inhibition of the integrase and reverse transcriptase of HIV-1 [18] and the NS3 protease of HCV [20]. PGG has been reported to exert its anti-HSV-1 and -IAV effects in association with autophagy [16,23]. The antiviral effect of PGG against RABV in vitro and in vivo was investigated, and its mechanism using mTOR-dependent autophagy to inhibit RABV replication was identified. Our results provide strong evidence showing that PGG has the potential to be used as an effective inhibitor of RABV replication
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