Acta Scientifica Malaysia (ASM)

Dengue is a clinically important arboviral disease and its global estimated burden is worrisome for the national and international health agencies. The Dengue virus (DENV) NS5 is the largest and most conserved non-structural protein among flaviviruses; for its crucial role in RNA synthesis and capping, it has been explored as a therapeutic target. In this review article, we have discussed the role of RNA capping and how it is critical for the viral RNA stability and evasion from the host immune sensors. With the structural information and mutagenesis studies describing DENV NS5 methyltransferase mechanistic role in sequential methylation, selective inhibitors for methyltransferase (MTase) domain have been identified. Despite, extensive studies, we could find only limited number of inhibitors targeting the capping process in vitro; but no clinically relevant inhibitors have been reported till date, particularly owed to the non-specificity and toxicity issues. In the future perspective section, we propose novel enzyme engineering strategies to develop a therapeutic protein that can be administered in severe Dengue cases to bring down the viral load. The proposed engineered MTase can have characteristics not only limited to enhanced affinity to viral RNA than native MTase and accomplishing defective or non-canonical methylation, that can render the viral RNA unstable or prone to host immune sensors. The engineered MTase can be delivered via state of art delivery systems such as nanoparticles, chimeric proteins, protein cages etc.