Zika Virus Genomic RNA Possesses Conserved G-Quadruplexes Characteristic of the Flaviviridae Family

Zika virus has emerged as a global concern because neither a vaccine nor antiviral compounds targeting it exist. A structure for the positive-sense RNA genome has not been established, leading us to look for potential G-quadruplex sequences (PQS) in the genome. The analysis identified >60 PQSs in the Zika genome. To minimize the PQS population, conserved sequences in the Flaviviridae family were found by sequence alignment, identifying seven PQSs in the prM, E, NS1, NS3, and NS5 genes. Next, alignment of 78 Zika strain genomes identified a unique PQS near the end of the 3'-UTR. Structural studies on the G-quadruplex sequences found four of the conserved Zika virus sequences to adopt stable, parallel-stranded folds that bind a G-quadruplex-specific compound, and one that was studied caused polymerase stalling when folded to a G-quadruplex. Targeting these PQSs with G-quadruplex binding molecules validated in previous clinical trials may represent a new approach for inhibiting viral replication.

[1]  R. Jain,et al.  Structure of NS3 helicase from Zika virus , 2016, Nature Structural &Molecular Biology.

[2]  Jean-Louis Mergny,et al.  Re-evaluation of G-quadruplex propensity with G4Hunter , 2016, Nucleic acids research.

[3]  G. Kuno,et al.  Full-length sequencing and genomic characterization of Bagaza, Kedougou, and Zika viruses , 2007, Archives of Virology.

[4]  G. Crooks,et al.  WebLogo: a sequence logo generator. , 2004, Genome research.

[5]  Jean-Louis Mergny,et al.  Thioflavin T as a fluorescence light-up probe for G4 formation , 2014, Nucleic acids research.

[6]  A. Benz,et al.  A comparison of DNA and RNA quadruplex structures and stabilities. , 2009, Bioorganic & medicinal chemistry.

[7]  L. Hurley,et al.  Biochemical techniques for the characterization of G-quadruplex structures: EMSA, DMS footprinting, and DNA polymerase stop assay. , 2010, Methods in molecular biology.

[8]  Jesse M. Platt,et al.  Detection of G-quadruplex DNA in mammalian cells , 2013, Nucleic acids research.

[9]  Jonathan B. Chaires,et al.  Kinetics and mechanism of K+- and Na+-induced folding of models of human telomeric DNA into G-quadruplex structures , 2008, Nucleic acids research.

[10]  Yi Shi,et al.  Zika virus NS1 structure reveals diversity of electrostatic surfaces among flaviviruses , 2016, Nature Structural &Molecular Biology.

[11]  R. Vorou.  Zika virus, vectors, reservoirs, amplifying hosts, and their potential to spread worldwide: what we know and what we should investigate urgently. , 2016, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases.

[12]  Stephen Neidle,et al.  Targeting G-quadruplexes in gene promoters: a novel anticancer strategy? , 2011, Nature Reviews Drug Discovery.

[13]  A. Gamarnik,et al.  RNA Structure Duplications and Flavivirus Host Adaptation. , 2016, Trends in microbiology.

[14]  M. Diamond,et al.  West Nile virus infection and immunity , 2013, Nature Reviews Microbiology.

[15]  H. Hauser,et al.  Translational Recoding Induced by G-Rich mRNA Sequences That Form Unusual Structures , 1996, Cell.

[16]  S. Balasubramanian,et al.  Insights into the mechanism of a G-quadruplex-unwinding DEAH-box helicase , 2015, Nucleic acids research.

[17]  N. Sugimoto,et al.  Monomorphic RNA G-quadruplex and polymorphic DNA G-quadruplex structures responding to cellular environmental factors. , 2010, Biochemistry.

[18]  B. Saccà,et al.  The effect of chemical modifications on the thermal stability of different G-quadruplex-forming oligonucleotides , 2005, Nucleic acids research.

[19]  Oleg Kikin,et al.  QGRS Mapper: a web-based server for predicting G-quadruplexes in nucleotide sequences , 2006, Nucleic Acids Res..

[20]  Abbreviations , 1971 .

[21]  Giorgio Palù,et al.  Anti-HIV-1 activity of the G-quadruplex ligand BRACO-19. , 2014, The Journal of antimicrobial chemotherapy.

[22]  T. Pierson,et al.  The 3.8 Å resolution cryo-EM structure of Zika virus , 2016, Science.

[23]  C. Burrows,et al.  A Role for the Fifth G-Track in G-Quadruplex Forming Oncogene Promoter Sequences during Oxidative Stress: Do These “Spare Tires” Have an Evolved Function? , 2015, ACS central science.

[24]  Shankar Balasubramanian,et al.  Prevalence of quadruplexes in the human genome , 2005, Nucleic acids research.

[25]  Christoph Nitsche,et al.  Crystal structure of Zika virus NS2B-NS3 protease in complex with a boronate inhibitor , 2016, Science.

[26]  Dinshaw J. Patel,et al.  Human telomere, oncogenic promoter and 5′-UTR G-quadruplexes: diverse higher order DNA and RNA targets for cancer therapeutics , 2007, Nucleic acids research.

[27]  T. Honda.  Links between Human LINE-1 Retrotransposons and Hepatitis Virus-Related Hepatocellular Carcinoma , 2016, Front. Chem..

[28]  Xiang Zhou,et al.  A highly conserved G-rich consensus sequence in hepatitis C virus core gene represents a new anti–hepatitis C target , 2016, Science Advances.

[29]  S. Kerwin,et al.  Simian virus 40 large T-antigen G-quadruplex DNA helicase inhibition by G-quadruplex DNA-interactive agents. , 2008, Biochemistry.

[30]  H. Lipps,et al.  G-quadruplexes and their regulatory roles in biology , 2015, Nucleic acids research.

[31]  Sudhir Kumar,et al.  MEGA7: Molecular Evolutionary Genetics Analysis Version 7.0 for Bigger Datasets. , 2016, Molecular biology and evolution.

[32]  C. Rice,et al.  Flavivirus genome organization, expression, and replication. , 1990, Annual review of microbiology.

[33]  Jean-Louis Mergny,et al.  How long is too long? Effects of loop size on G-quadruplex stability , 2010, Nucleic acids research.

[34]  Erik Wright,et al.  DECIPHER: harnessing local sequence context to improve protein multiple sequence alignment , 2015, BMC Bioinformatics.

[35]  Jie Zhong,et al.  G-quadruplexes regulate Epstein-Barr virus-encoded nuclear antigen 1 mRNA translation. , 2014, Nature chemical biology.

[36]  Jesse M. Platt,et al.  Detection of G-quadruplex DNA in mammalian cells , 2017, Nucleic acids research.

[37]  S. Balasubramanian,et al.  Quantitative visualization of DNA G-quadruplex structures in human cells. , 2013, Nature chemistry.