Article Preview
Top1. Introduction
Vector-borne contagious diseases refer to contaminations that are transmitted through a disease-vector. A disease-vector is a living carrier, usually, blood-sucking insects such as mosquitoes, fly and tick having the ability to transmit pathogens between vertebrate hosts, including humans (Verwoerd et al., 2015). Vector-borne infections are viewed as a noteworthy worldwide threat to public health as they cause over one million deaths annually, and more than one billion individuals get tainted every year. Since 2014, major outbreaks of dengue, malaria, chikungunya, yellow fever, and Zika have afflicted populations, claimed lives and overwhelmed health systems in many countries (Müller et al., 2019). There have been proper medicines to control these diseases except the Zika virus which is very devastating. The two prominent strains of the Zika virus are identified as African lineage of Zama virus and the Asian lineage of the Zika virus. The African lineage of the Zama virus infects human neural progenitor cells and might be progressively dangerous to early placenta because of its exceptionally tropic conduct in primitive trophoblast and because of its capacity to separate the cells. The Asian lineage of Zika virus that infected the Brazilian civilians with sharing a common ancestry to French Polynesian strain was found to cause brain development abnormalities (Bayer et al. 2016; Sheridan et al. 2016). It was followed by the announcement of the public health emergency of international concern (PHEIC) around the present outbreak on February 2, 2016 (Grenoble et al. 2016). Therefore, researchers have studied in depth to discover the mechanism of Zika viral targets responsible for the dreadful virulence.
Zika is an arthropod-virus, which has a place with the flavivirus of the family Flaviviridae. The vector from Yellow fever, West Nile Virus (WNV), Dengue Virus (DENV) and Japanese Encephalitis virus (JEV) belong to the same family members having different potential targets such as NS5 methyltransferase, NS5 RNA-dependent RNA-polymerase (RdRp), ZIKV protease (NS3 and NS2B-NS3 Protease), NS3 helicase domain, Capsid (C) and Envelope (E) proteins. Recently a review was published to explore the update of various targets and their potential inhibitors (Nandi et al., 2019). Very recently, Ferrero et al. (2019) developed a crystal structure of the NS5 protein from full-length Zika infection by taking human isolate Z1106033. A non-structural bifunctional enzyme is represented by NS5 protein having methyltransferase at its N-terminal end. The MTase present in the protein is answerable for viral genomic replication of 5’ end (Dong et al., 2008). The NS5 is the biggest nonstructural protein that posses S-adenosyl-L-methionine (SAM)-dependent methyltransferase (MTase) at N-terminus and an RNA-dependent RNA polymerase (RdRP) at its C-terminal. Both ending domains have an S-adenosyl-methionine subordinate methyltransferase focus structure that folds into an α/β/α sheet held between N and C terminal subdomains. The central part is responsible for viral genome replication with the RdRP and genome RNA topping with the MTase spot respectively (Duan et al., 2017). The NS5 MTase has explicit binding sites for both RNA and SAM. It is a common binding site for the GTP and RNA cap. The perplexing structures with substrates/items are accessible for some flaviviruses, and also ZIKV NS5 MTase structure along with the co-crystals SAM and 7meGpp ligand was finally solved recently (Coloma et al. 2016). The NS5-methyltransferase plays a crucial role in RNA synthesis that is needed for the replication process of ZIKV, DENV, WNV, JEV, yellow fever, and chikungunya. At present, there is no particular drug to kill zika virus. The methyltransferase inhibitors which are used for the treatment of dengue virus and West Nile virus could be repurposed to combat zika virus.
In the present attempt, 25 potential compounds having MTase inhibitory activities against dengue virus and West Nile virus are taken from the literatures, and the mode of binding of these compounds was studied utilizing in-silico structure-based molecular docking. Then, a comparative study of the mode of interactions of sinefungin (potential natural lead inhibitor of Zika virus and 25 MTase inhibitors was done. The mode of binding similarities between standard sinefungin and methyltransferase inhibitors were observed.