Therapeutic Potential of Medicinal Plants against Dengue Infection: A Mechanistic Viewpoint

Abstract

Dengue is a tropical disease caused by the Dengue virus (DENV), a positive-sense, single stranded RNA virus of the family Flaviviridae, which is transmitted by Aedes mosquitoes. The occurrence of dengue has grown dramatically around the globe in recent decades, and it is rapidly becoming a global burden. Furthermore, all four DENV serotypes cocirculate and create a problematic hyperendemic situation. Characteristic symptoms range from being asymptomatic, dengue fever to life-threatening complications such as hemorrhagic fever and shock. Apart from the inherent virulence of the virus strain, a dysregulated host immune response makes the condition worse. Currently, there is no highly recommended vaccine or therapeutic agent against dengue. With the advent of virus strains resistant to antiviral agents, there is a constant need for new therapies to be developed. Since time immemorial, human civilization has utilized plants in traditional medicine to treat various diseases, including infectious viral diseases. With the advancement in molecular biology, cell biology techniques, and bioinformatics, recent studies have tried to provide scientific evidence and determine the mechanism of anti-dengue activity of various plant extracts and plant-derived agents. The current Review consolidates the studies on the last 20 years of in vitro and in vivo experiments on the ethnomedicinal plants used against the dengue virus. Several active phytoconstituents like quercetin, castanospermine, α-mangostin, schisandrin-A, hirsutin have been found to be promising to inhibition of all the four DENV serotypes. However, novel therapeutics need to be reassessed in relevant cells using high-throughput techniques. Further, in vivo dose optimization for the immunomodulatory and antiviral activity should be examined on a vast sample size. Such a Review should help take the knowledge forward, validate it, and use medicinal plants in different combinations targeting multiple stages of virus infection for more effective multipronged therapy against dengue infection.

Figure 1

Depiction of the life cycle of DENV and potential antidengue drug target sites. (1) Attachment: The E protein of DENV binds to a specific receptor of host cells. (2) Endocytosis: the virus is taken up by clathrin-mediated endocytosis. (3) Fusion: DENV E encounters acidic pH in the endosome, which changes the conformation of E protein catalyzing fusion of virus and endosome membrane and releasing DENV RNA into host cytoplasm. (4) Virus RNA translation and replication. (5) Assembly: virus proteins assemble with viral genome. (6) Maturation: E protein in immature virus in TGN is cleaved by host furin protease resulting in mature DENV. (7) DENV release by budding. (8) Host immune response.

Figure 2

Steps of human innate immune response after sensing dengue viral RNA inside the cell. (A) RIG-I mediated cytoplasmic response (B) Toll-like receptor (TLR-3 and TLR-7) mediated endosomal response. Abbreviations: ssRNA = single-stranded RNA; dsRNA = double stranded RNA; RIG-I = retinoic acid-inducible gene I receptor; MAVS = mitochondrial antiviral-signaling protein; sfRNA= subgenomic flavivirus RNA; IFN = Interferon; IRF = interferon regulatory factor; TRIF = TIR-domain-containing adapter-inducing IFNβ; TRAF = TNF-receptor-associated factor; MyD88 = Myeloid differentiation responsive gene 88; IKK = IκB kinase complex (α, β, γ, and ε); TBK = TANK-binding kinase; NF-Κb = Nuclear factor kappa B.

Figure 3

Immune response observed in mild and severe dengue disease.

Figure 4

Assays used for assessing antiviral activity.

Figure 5

Molecular structure of some phytoconstituents or active compounds with already known antidengue activity.