In Silico Design of siRNAs for Silencing CLEC5A Receptor as a Potential Therapeutic Approach Against Dengue and Japanese Encephalitis Virus Infection in Human

Abstract

Dengue and Japanese encephalitis virus (JEV) are mosquito-borne RNA viruses that can cause severe illness leading to death in the tropics and subtropics. Both of these viruses interact directly with the C-type lectin domain family 5, member A receptor (CLEC5A) on human macrophages which stimulates the release of proinflammatory cytokines. Since blockade of this interaction has been shown to suppress the secretion of cytokines, CLEC5A is considered a potential target for the development of new treatments to reduce virus-induced brain damage. Developing a vaccine against dengue is challenging because this virus can cause disease through 4 different serotypes. Therefore, the vaccine must immunize against all 4 serotypes to be effective, while unvaccinated people still contract JEV and suffer from its complications. Small interfering RNAs (siRNAs) play an important role in regulating gene expression by causing the degradation of target mRNAs. In this study, we attempted to rationally design potential siRNA molecules using various software, targeting the CLEC5A gene. In total, 3 siRNAs were found to be potential candidates for CLEC5A silencing. They showed good target accessibility, optimum guanine-cytosine (GC) content, the least chance of off-target effects, positive energy of folding, and strong interaction with Argonaute2 protein as denoted by a negative docking energy score. In addition, molecular dynamics simulation of the siRNA-Ago2-docked complexes showed the stability of the complexes over 1.5 nanoseconds. These predicted siRNAs might effectively downregulate the expression of the CLEC5A receptor and thus prove vital in the treatment of dengue and JEV infections.