Progress in the Identification of Dengue Virus Entry/Fusion Inhibitors

Abstract

Dengue fever, a reemerging disease, is putting nearly 2.5 billion people at risk worldwide. The number of infections and the geographic extension of dengue fever infection have increased in the past decade. The disease is caused by the dengue virus, a flavivirus that uses mosquitos Aedes sp. as vectors. The disease has several clinical manifestations, from the mild cold-like illness to the more serious hemorrhagic dengue fever and dengue shock syndrome. Currently, there is no approved drug for the treatment of dengue disease or an effective vaccine to fight the virus. Therefore, the search for antivirals against dengue virus is an active field of research. As new possible receptors and biological pathways of the virus biology are discovered, new strategies are being undertaken to identify possible antiviral molecules. Several groups of researchers have targeted the initial step in the infection as a potential approach to interfere with the virus. The viral entry process is mediated by viral proteins and cellular receptor molecules that end up in the endocytosis of the virion, the fusion of both membranes, and the release of viral RNA in the cytoplasm. This review provides an overview of the targets and progress that has been made in the quest for dengue virus entry inhibitors.

Dengue Virus Entry and Trafficking: Perspectives as Antiviral Target for Prevention and Therapy

“…In addition, the blockage of virus entry will potentially limit the viremia and the hyperactivation of the immune system resulting in the prevention of severe dengue and reducing DENV transmission. Different approaches have been employed to identify inhibitors of DENV entry into the host cell, including screening of natural and synthetic molecules based in viral replication studies, structure-based rational design of molecules that interact either with E protein or cellular receptors and virtual screening of small molecules from different chemical databases [7,103]. Those antiviral molecules that target viral components are more specific and selective inhibitors, whereas targeting cellular factors reduces the risk of resistance development and would be useful for viruses that share the requirement of the same cellular process or factor for replication.…”

“…future science group www.futuremedicine.com receptor interaction [103,116]. A great variety of polysaccharides such as DL-galactan hybrids, fucoidans and carrageenans, obtained from marine algae, display anti-DENV-2 activity [20,46,[117][118][119].…”

“…Most of the developed inhibitors await in vivo experimentation and certainly, the lack of a simple small animal model has been one of the major weaknesses for the rapid development of antiviral agents against DENV [103,145]. Chloroquine was the only entry-targeted compound that has attained clinical testing, but with disappointing results.…”

Structure-Based Mutational Analysis of Several Sites in the E Protein: Implications for Understanding the Entry Mechanism of Japanese Encephalitis Virus

“…In fact, many useful DENV-targeting compounds blocking these regions of the viral entry pathway have been identified (69). Because JEV shares a high percentage of amino acids in the E protein with the other flaviviruses, more work on the identification and characterization of critical amino acids in the E protein may provide a novel theoretical basis for drug and vaccine design for flaviviruses.…”

Genomic studies of envelope gene sequences from mosquito and human samples from Bangkok, Thailand

“…Dengue virus (DENV) is a single-stranded positive-sense RNA virus belonging to genus Flavivirus of family Flaviviridae (De la Guardia and Lleonart 2014). This virus is the causative agent of dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS), which is transmitted by infected female Aedes aegypti mosquitoes and seasonally epidemic in Thailand.…”