Importance of Zika Virus NS5 Protein for Viral Replication

Abstract

Zika virus is the latest addition to an ever-growing list of arboviruses that are causing outbreaks with serious consequences. A few mild cases were recorded between 1960 and 1980 until the first major outbreak in 2007 on Yap Island. This was followed by more severe outbreaks in French Polynesia (2013) and Brazil (2015), which significantly increased both Guillain-Barre syndrome and microcephaly cases. No current vaccines or treatments are available, however, recent studies have taken interest in the NS5 protein which encodes both the viral methyltransferase and RNA-dependent RNA polymerase. This makes it important for viral replication alongside other important functions such as inhibiting the innate immune system thus ensuring virus survival and replication. Structural studies can help design inhibitors, while biochemical studies can help understand the various mechanisms utilized by NS5 thus counteracting them might inhibit or abolish the viral infection. Drug repurposing targeting the NS5 protein has also proven to be an effective tool since hundreds of thousands of compounds can be screened therefore saving time and resources, moreover information on these compounds might already be available especially if they are used to treat other ailments.

Identification and Characterization of Zika Virus NS5 Methyltransferase Inhibitors

“…Among the nonstructural proteins, NS5 is the largest enzyme including 904 amino acids ( Issur et al., 2009 ; Piorkowski et al., 2016 ). It consists of 2 domains: an RNA-dependent RNA polymerase (RdRp) domain at the C-terminal and a methyltransferase (MTase) domain at the N-terminal ( Elshahawi et al., 2019 ). The NS5 RdRp domain contributes to the viral RNA synthesis through a de novo initiation mechanism ( Godoy et al., 2017 ).…”

Zika Virus-Induction of the Suppressor of Cytokine Signaling 1/3 Contributes to the Modulation of Viral Replication

“…The ZIKV genome is comprised of three structural (C, prM, and E) and seven non-structural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) [6,7]. Flaviviruses utilize diverse strategies involving NS proteins to suppress interferon (IFN)-mediated pathways.…”

Zika Virus Pathogenesis: A Battle for Immune Evasion

“…ZIKV NS5 is the most highly conserved protein encoded by ZIKV genome not only because of the requirement to maintain two enzymatic activities indispensable for virus replication, methyltransferase and RNA-dependent RNA polymerase, but also in its IFN-I antagonism [ 173 , 236 , 237 , 238 , 239 , 240 ].…”