(E)-Guggulsterone Inhibits Dengue Virus Replication by Upregulating Antiviral Interferon Responses through the Induction of Heme Oxygenase-1 Expression

Abstract

Dengue virus (DENV) infection, which causes dengue fever, dengue hemorrhagic fever, and dengue shock syndrome, is a severe global health problem in tropical and subtropical areas. There is no effective vaccine or drug against DENV infection. Thus, the development of anti-DENV agents is imperative. This study aimed to assess the anti-DENV activity of (E)-guggulsterone using a DENV infectious system. A specific inhibitor targeting signal molecules was used to evaluate the molecular mechanisms of action. Western blotting and qRT-PCR were used to determine DENV protein expression and RNA replication, respectively. Finally, an ICR suckling mouse model was used to examine the anti-DENV activity of (E)-guggulsterone in vivo. A dose-dependent inhibitory effect of (E)-guggulsterone on DENV protein synthesis and RNA replication without cytotoxicity was observed. The mechanistic studied revealed that (E)-guggulsterone stimulates Nrf2-mediated heme oxygenase-1 (HO-1) expression, which increases the antiviral interferon responses and downstream antiviral gene expression by blocking DENV NS2B/3B protease activity. Moreover, (E)-guggulsterone protected ICR suckling mice from life-threatening DENV infection. These results suggest that (E)-guggulsterone can be a potential supplement for controlling DENV replication.

Computational Bioprospecting Guggulsterone against ADP Ribose Phosphatase of SARS-CoV-2

“…Isolated guggulsterone, as the major constituent of the C. gileadensis extract, exhibited antiviral activity against Dengue virus (DENV) [ 69 ], herpes simplex virus type 2 (HSV-2), respiratory syncytial virus type B (RSV-B), coxsackie virus B type 3, and adenovirus type 5 [ 70 ]. Guggulsterone was also previously reported in the literature for its potential beneficial effects against COVID-19 disease [ 71 , 72 ].…”

Modulation of immune responses in the central nervous system by Zika virus, West Nile virus, and dengue virus

“…For instance, the DENV nonstructural protein 5 (NS5) has been shown to interfere with type I IFN signalling by targeting key components of the Janus kinase (JAK)‐signal transducer and STAT pathway, thereby dampening antiviral responses in infected cells 32 . Additionally, the DENV envelope (E) protein can activate the nuclear factor kappa B (NF‐κB) pathway, leading to the production of proinflammatory cytokines and exacerbating neuroinflammation in the CNS 33 …”

Phytochemicals as Invaluable Sources of Potent Antimicrobial Agents to Combat Antibiotic Resistance

“…Subsequent bio-guided assays revealed that the leaf extract contains guggulsterone as the active compound. Chen et al, (2021) investigated the antiviral activity of guggulsterone against DENV and found that guggulsterone inhibited protein synthesis and RNA replication in DENV in a dose-dependent manner [210]. In vivo analysis in a ICR suckling mouse model demonstrated that guggulsterone stimulates the Nrf2-driven expression of heme oxygenase-1 to increase antiviral interferon response [210].…”

“…Chen et al, (2021) investigated the antiviral activity of guggulsterone against DENV and found that guggulsterone inhibited protein synthesis and RNA replication in DENV in a dose-dependent manner [210]. In vivo analysis in a ICR suckling mouse model demonstrated that guggulsterone stimulates the Nrf2-driven expression of heme oxygenase-1 to increase antiviral interferon response [210]. Hemeoxygenase-1 is a host antioxidant enzyme that breakdowns the heme ring into biliverdin.…”