Challenges and perspectives in the discovery of dengue virus entry inhibitors

Abstract

Dengue virus (DENV) disease has become one of the major challenges inpublic health. Currently, there is no antiviral treatment for this infection. Since humantransmission occurs via mosquitoes of the Aedes genus, most efforts have been focusedon the control of this vector. However, these control strategies have not been totally successful,as reflected in the increasing number of DENV infections per year, becoming anendemic disease in more than 100 countries worldwide. Consequently, the developmentof a safe antiviral agent is urgently needed. In this sense, rational design approaches havebeen applied in the development of antiviral compounds that inhibit one or more steps inthe viral replication cycle.The entry of viruses into host cells is an early and specific stage of infection. Targeting eitherviral components or cellular protein targets are an affordable and effective strategyfor therapeutic intervention of viral infections.This review provides an extensive overview of the small organic molecules, peptides,and inorganic moieties that have been tested so far as DENV entry direct-acting antiviralagents. The latest advances based on computer-aided drug design (CADD) strategies andtraditional medicinal chemistry approaches in the design and evaluation of DENV virusentry inhibitors will be discussed. Furthermore, physicochemical drug properties, such assolubility, lipophilicity, stability, and current results of pre-clinical and clinical studieswill also be discussed in detail.