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Review
. 2023 Mar 8;15(3):705.
doi: 10.3390/v15030705.

Molecular Mechanisms of Antiviral Agents against Dengue Virus

Michelle Felicia Lee  1 , Yuan Seng Wu  1 , Chit Laa Poh  1
Affiliations
Review

Molecular Mechanisms of Antiviral Agents against Dengue Virus

Michelle Felicia Lee et al. Viruses. .

Abstract

Dengue is a major global health threat causing 390 million dengue infections and 25,000 deaths annually. The lack of efficacy of the licensed Dengvaxia vaccine and the absence of a clinically approved antiviral against dengue virus (DENV) drive the urgent demand for the development of novel anti-DENV therapeutics. Various antiviral agents have been developed and investigated for their anti-DENV activities. This review discusses the mechanisms of action employed by various antiviral agents against DENV. The development of host-directed antivirals targeting host receptors and direct-acting antivirals targeting DENV structural and non-structural proteins are reviewed. In addition, the development of antivirals that target different stages during post-infection such as viral replication, viral maturation, and viral assembly are reviewed. Antiviral agents designed based on these molecular mechanisms of action could lead to the discovery and development of novel anti-DENV therapeutics for the treatment of dengue infections. Evaluations of combinations of antiviral drugs with different mechanisms of action could also lead to the development of synergistic drug combinations for the treatment of dengue at any stage of the infection.

Keywords: antiviral; dengue virus; flavivirus; mechanism of action; peptide; phytochemicals; small molecule.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
DENV RNA genome organization. The DENV positive-sense RNA genome consists of 11 kilobases (kb) with a single open reading frame (ORF) characterized by the presence of two untranslated regions (UTRs) at both ends of the ORF. The 5′-UTR consists of 95–135 nucleotides with a type I cap-like mRNA whereas the 3′-UTR consists of 114–650 nucleotides and lacks a poly(A) tail, ending in a conserved stem-loop secondary structure [23,24]. The figure was created using Biorender.com (ON, Canada) (accessed on 26 February 2023).
Figure 2
Figure 2
DENV life cycle. (a) DENV viral particles attach to the host cells via interactions between DENV surface proteins and their respective host receptors. (b) DENV enters host cells via receptor-mediated or clathrin-dependent endocytosis. (c) pH-dependent membrane fusion occurs in the endosome and this results in the formation of pores which allows the release of the DENV viral genome into the host cytoplasm. (d) The released viral RNA is translated into a polyprotein in the host cytoplasm. (e) Viral assembly takes place at the ER to form immature DENV virions. (f) These immature DENV particles travel through the secretory pathway and TGN to form mature DENV virions. (g) Following successful virus maturation, the mature DENV particles are then exocytosed from the host cells. The figure was created using Biorender.com (accessed on 7 March 2023).
Figure 3
Figure 3
DENV host receptors as potential antiviral targets. Several molecules identified as possible host cellular receptors or attachment factors for DENV include heparan sulfate, mannose, DC-SIGN, laminin, HSP90/HSP70, and TIM and TAM proteins. The figure was created using Biorender.com (accessed on 26 February 2023).
Figure 4
Figure 4
General molecular mechanism of compounds (labelled C) targeting DENV NS5. The binding of these compounds to DENV NS5 MTase and RdRp could possibly block the viral RNA synthesis step, resulting in inhibition of viral replication and reduced DENV production. The figure was created using Biorender.com (accessed on 7 March 2023).
See this image and copyright information in PMC

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