Abstract
Dengue virus (DENV) presents a significant threat to global public health with more than 500,000 hospitalizations and 25,000 deaths annually. Currently, there is no clinically approved antiviral drug to treat DENV infection. The envelope (E) glycoprotein of DENV is a promising target for drug discovery as the E protein is important for viral attachment and fusion. Understanding the structure and function of DENV E protein has led to the exploration of structure-based drug discovery of antiviral compounds and peptides against DENV infections. This review summarizes the structural information of the DENV E protein with regards to DENV attachment and fusion. The information enables the development of antiviral agents through structure-based approaches. In addition, this review compares the potency of antivirals targeting the E protein with the antivirals targeting DENV multifunctional enzymes, repurposed drugs and clinically approved antiviral drugs. None of the current DENV antiviral candidates possess potency similar to the approved antiviral drugs which indicates that more efforts and resources must be invested before an effective DENV drug materializes.
Highlights
Dengue virus (DENV) infection is the most prevalent arboviral disease with 390 million infections occurring annually, of which 96 million infections were manifested clinically [1]
In the structure-based rational design approach, researchers designed new peptides mimicking the specific regions in DENV such as the envelope glycoprotein, capsid protein and viral enzymes based on the available 3D structures
No antiviral agent has been demonstrated to be effective against acute dengue in clinical trials, the pre-clinical research pipeline contains many antiviral agents that are promising
Summary
Dengue virus (DENV) infection is the most prevalent arboviral disease with 390 million infections occurring annually, of which 96 million infections were manifested clinically [1]. Infection with any of the four DENV serotypes (DENV1-4) can produce a range of clinical manifestations, from a mild flu-like illness to life-threatening severe diseases known as dengue haemorrhagic fever (DHF). Vaccines and antiviral therapies are being developed to prevent or treat DENV infection. Dengvaxia was shown to increase the risk of dengue hospitalizations in seronegative vaccinees in comparison to unvaccinated seronegative individuals [6]. An increased risk of severe dengue has been observed in seronegative vaccine recipients during subsequent infection with other heterologous DENV serotypes [5]. The development of effective antiviral agents against DENV infection is being widely pursued. There is a resurgence in the peptide-based drug research to develop effective antiviral peptides against viruses following the success of the commercially available enfuvirtide [7]. Enfuvirtide blocks the fusion of HIV-1 and cellular membranes by binding to the HIV gp
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