Functional Information Stored in the Conserved Structural RNA Domains of Flavivirus Genomes

Abstract

The genus Flavivirus comprises a large number of small, positive-sense single-stranded, RNA viruses able to replicate in the cytoplasm of certain arthropod and/or vertebrate host cells. The genus, which has some 70 member species, includes a number of emerging and re-emerging pathogens responsible for outbreaks of human disease around the world, such as the West Nile, dengue, Zika, yellow fever, Japanese encephalitis, St. Louis encephalitis, and tick-borne encephalitis viruses. Like other RNA viruses, flaviviruses have a compact RNA genome that efficiently stores all the information required for the completion of the infectious cycle. The efficiency of this storage system is attributable to supracoding elements, i.e., discrete, structural units with essential functions. This information storage system overlaps and complements the protein coding sequence and is highly conserved across the genus. It therefore offers interesting potential targets for novel therapeutic strategies. This review summarizes our knowledge of the features of flavivirus genome functional RNA domains. It also provides a brief overview of the main achievements reported in the design of antiviral nucleic acid-based drugs targeting functional genomic RNA elements.

Long non‐coding subgenomic flavivirus RNAs have extended 3D structures and are flexible in solution

“…Due to the lack of effective antiviral drugs and vaccines against these viruses, they pose a significant threat to human health and are serious concerns in many parts of the world [8]. The ORF encodes a polyprotein which is cotranslationally and/or posttranslationally processed into three structural proteins (capsid, pre-membrane/membrane, and envelope) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) [9]. The ORF encodes a polyprotein which is cotranslationally and/or posttranslationally processed into three structural proteins (capsid, pre-membrane/membrane, and envelope) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) [9].…”

“…Flaviviruses are enveloped RNA viruses with singlestranded, positive sense genomic RNA (gRNA) of approximately 10-11 kb in length which consists of a single open reading frame (ORF) flanked by highly structured 5 0 and 3 0 untranslated regions (UTR). The 5 0 UTR, 3 0 UTR, and capsid coding sequences are highly structured and contain many cis-acting elements which are involved in gRNA replication, translation, and perhaps encapsidation [9][10][11]. The 5 0 UTR, 3 0 UTR, and capsid coding sequences are highly structured and contain many cis-acting elements which are involved in gRNA replication, translation, and perhaps encapsidation [9][10][11].…”

“…Flaviviruses are enveloped RNA viruses with singlestranded, positive sense genomic RNA (gRNA) of approximately 10-11 kb in length which consists of a single open reading frame (ORF) flanked by highly structured 5 0 and 3 0 untranslated regions (UTR). The ORF encodes a polyprotein which is cotranslationally and/or posttranslationally processed into three structural proteins (capsid, pre-membrane/membrane, and envelope) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) [9]. The 5 0 UTR, 3 0 UTR, and capsid coding sequences are highly structured and contain many cis-acting elements which are involved in gRNA replication, translation, and perhaps encapsidation [9][10][11].…”

“…It has been reported that an incomplete degradation of the flavivirus gRNA by stalling of the cellular 5 0 ?3 0 exonuclease Xrn1 near the beginning of the 3 0 UTR is responsible for the production of an abundance of long non-coding subgenomic flavivirus RNAs (sfRNA) ranging from 300 to 500 nt in length during infection [9,12]. In DENV2, the 3 0 UTR is structurally divided into five independently folded subdomains: SLI, SLII, DB1, DB2, and the essential terminal structure 3 0 SL ( Fig 1A) [13].…”

Nanoscale Structure Determination of Murray Valley Encephalitis and Powassan Virus Non-coding RNAs

“…Flaviviruses include deadly viruses such as Murray Valley Encephalitis Virus (MVEV), Powassan Virus (PowV), Japanese encephalitis virus, Dengue virus, Zika virus, West Nile virus and Yellow Fever virus. The World Health Organization and the Centers for Disease Control both cite flaviviruses as a global health threat owing to the ease of transmission by mosquitoes and lack efficient therapeutic or immunoprophylactic strategies [1]. Given the magnitude and severity of disease from this class of viruses, there is a critical need for therapeutics; however, the limited understanding of the virus's replication and their complex interactions with the host cellular proteins through terminal region (TR) interactions hinders therapeutic development [2][3][4].…”