Recent advances in natural products as potential inhibitors of dengue virus with a special emphasis on NS2b/NS3 protease.

Dengue virus (DENV) is an arbovirus widespread through tropical and subtropical areas. It is transmitted to humans through Aedes mosquitoes. Infections with DENV can lead to a series of complications, including dengue fever, dengue haemorrhagic fever, or dengue shock syndrome, which might manifest through secondary infections because of a vulnerable immune system. To date, only one tetravalent DENV vaccine is approved to be administered to children whom have been previously DENV-infected and between 9 and 16 years of age. One of the key targets in discovering DENV antiviral agents is the NS2b/NS3 protease. This protease is a crucial enzyme complex for the proteolytic and cleavage activities of the translated polyprotein during DENV life cycle. Several studies were conducted to discover potential antivirals from natural sources or synthetic compounds and peptides. In this review, we describe the recent studies from the past five years dealing with isolated natural products as potential inhibitors of DENV with a greater focus on inhibiting the NS2b/NS3 protease. This review describes recent discoveries in anti-DENV potential of isolated phytochemicals belonging to different groups including fatty acids, glucosides, terpenes and terpenoids, flavonoids, phenolics, chalcones, acetamides, and peptides. Curcumin, quercetin, and myricetin were found to act as non-competitive inhibitors for the NS2b/NS3 protease enzyme. In some studies, the molecular targets of some of these compounds are yet to be identified using in-silico and in-vitro approaches. So far, none of the isolated natural products was tested clinically for the management of DENV infections. The discussed studies demonstrate that natural products are a rich source of potential anti-DENV compounds. However, not all of these compounds were studied for their kinetic molecular mechanism and type of inhibition. In-silico studies provided an ample number of phytochemical hits to be tested experimentally as DENV protease inhibitors. In conclusion, derivatives of these natural products can be designed and synthesised, which could enhance their specificity and efficacy towards the protease. Other sources of natural products, such as fungi, bacterial toxins, marine organisms, and animals, should also be explored towards discovering more potential and effective DENV NS2b/NS3 protease inhibitors.