Approximately 100–400 million people from more than 100 countries in the tropical and subtropical world are affected by dengue infections. Recent scientific breakthroughs have brought new insights into novel strategies for the production of dengue antivirals and vaccines. The search for specific dengue inhibitors is expanding, and the mechanisms for evaluating the efficacy of novel drugs are currently established, allowing for expedited translation into human trials. Furthermore, in the aftermath of the only FDA-approved vaccine, Dengvaxia, a safer and more effective dengue vaccine candidate is making its way through the clinical trials. Until an effective antiviral therapy and licensed vaccine are available, disease monitoring and vector population control will be the mainstays of dengue prevention. In this article, we highlighted recent advances made in the perspectives of efforts made recently, in dengue vaccine development and dengue antiviral drug.

An increase in the occurrence of viral infectious diseases is a global concern for human health. According to a WHO report, dengue virus (DENV) is one of the most common viral diseases affecting approximately 400 million people annually, with worsening symptoms in nearly 1% of cases. Both academic and industrial researchers have conducted numerous studies on viral epidemiology, virus structure and function, source and route of infection, treatment targets, vaccines, and drugs. The development of CYD-TDV or Dengvaxia^®vaccine has been a major milestone in dengue treatment. However, evidence has shown that vaccines have some drawbacks and limitations. Therefore, researchers are developing dengue antivirals to curb infections. DENV NS2B/NS3 protease is a DENV enzyme essential for replication and virus assembly, making it an interesting antiviral target. For faster hit and lead recognition of DENV targets, methods to screen large number of molecules at lower costs are essential. Similarly, an integrated and multidisciplinary approach involvingin silicoscreening and confirmation of biological activity is required. In this review, we discuss recent strategies for searching for novel DENV NS2B/NS3 protease inhibitors from thein silicoandin vitroperspectives, either by applying one of the approaches or by integrating both. Therefore, we hope that our review will encourage researchers to integrate the best strategies and encourage further developments in this area.

Dengue is a neglected disease caused by the infection of dengue virus which is transmitted by Aedes mosquitoes and to some, it could be fatal. Regardless of the enormous work devoted to research for the treatment of dengue, to this day there is no cure, and treatment is solely limited to supportive care by treating the symptoms. The inhibition of the viral RNA non-structural enzymes has been the most popular approach amongst the strategies applied to the search and development of dengue antivirals. This review is a compact digest of what is already known of the roles and the prospects of the dengue virus non-structural proteins NS1, NS2BNS3, NS4A, NS4B and NS5 as the targets for antiviral studies including the recent progress that has been published regarding their roles.

Dibutyl phthalate (DBP) produced by Streptomyces sp. H11809 exerted inhibitory activity against human GSK-3β (Hs GSK-3β) and Plasmodiumfalciparum 3D7 (Pf 3D7) malaria parasites. The current study aimed to determine DBP’s plausible mode of action against Hs GSK-3β and Pf 3D7. Molecular docking analysis indicated that DBP has a higher binding affinity to the substrate-binding site (pocket 2; −6.9 kcal/mol) than the ATP-binding site (pocket 1; −6.1 kcal/mol) of Hs GSK-3β. It was suggested that the esters of DBP play a pivotal role in the inhibition of Hs GSK-3β through the formation of hydrogen bonds with Arg96/Glu97 amino acid residues in pocket 2. Subsequently, an in vitro Hs GSK-3β enzymatic assay revealed that DBP inhibits the activity of Hs GSK-3β via mixed inhibition inhibitory mechanisms, with a moderate IC₅₀ of 2.0 µM. Furthermore, the decrease in K_m value with an increasing DBP concentration suggested that DBP favors binding on free Hs GSK-3β over its substrate-bound state. However, the antimalarial mode of action of DBP remains unknown since the generation of a Pf 3D7 DBP-resistant clone was not successful. Thus, the molecular target of DBP might be indispensable for Pf survival. We also identified nocardamine as another active compound from Streptomyces sp. H11809 chloroform extract. It showed potent antimalarial activity with an IC₅₀ of 1.5 μM, which is ~10-fold more potent than DBP, but with no effect on Hs GSK-3β. The addition of ≥12.5 µM ferric ions into the Pf culture reduced nocardamine antimalarial activity by 90% under in vitro settings. Hence, the iron-chelating ability of nocardamine was shown to starve the parasites from their iron source, eventually inhibiting their growth.