A Polyamide Inhibits Replication of Vesicular Stomatitis Virus by Targeting RNA in the Nucleocapsid

Gumpper, Ryan H.; Li, Weike; Castañeda, Carlos H.; Scuderi, M. José; Bashkin, James K.; Luo, Ming

doi:10.1128/JVI.00146-18

Title: A Polyamide Inhibits Replication of Vesicular Stomatitis Virus by Targeting RNA in the Nucleocapsid

Journal Article · Wed Feb 07 00:00:00 EST 2018 · Journal of Virology

DOI:https://doi.org/10.1128/JVI.00146-18· OSTI ID:1433705

Gumpper, Ryan H. ^[1]; Li, Weike ^[1]; Castañeda, Carlos H. ^[2]; Scuderi, M. José ^[2]; Bashkin, James K. ^[2]; Luo, Ming ^[1]

Georgia State Univ., Atlanta, GA (United States)
Univ. of Missouri, St. Louis, MO (United States)

Polyamides have been shown to bind double-stranded DNA by complementing the curvature of the minor groove and forming various hydrogen bonds with DNA. Several polyamide molecules have been found to have potent antiviral activities against papillomavirus, a double-stranded DNA virus. By analogy, we reason that polyamides may also interact with the structured RNA bound in the nucleocapsid of a negative-strand RNA virus. For this work, Vesicular stomatitis virus (VSV) was selected as a prototype virus to test this possibility since its genomic RNA encapsidated in the nucleocapsid forms a structure resembling one strand of an A-form RNA duplex. One polyamide molecule, UMSL1011, was found to inhibit infection of VSV. To confirm that the polyamide targeted the nucleocapsid, a nucleocapsid-like particle (NLP) was incubated with UMSL1011. The encapsidated RNA in the polyamide-treated NLP was protected from thermo-release and digestion by RNase A. UMSL1011 also inhibits viral RNA synthesis in the intracellular activity assay for the viral RNA-dependent RNA polymerase. The crystal structure revealed that UMSL1011 binds the structured RNA in the nucleocapsid. The conclusion of our studies is that the RNA in the nucleocapsid is a viable antiviral target of polyamides. Since the RNA structure in the nucleocapsid is similar in all negative-strand RNA viruses, polyamides may be optimized to target the specific RNA genome of a negative-strand RNA virus, such as respiratory syncytial virus and Ebola virus.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); University of Missouri Research Board; National Science Foundation (NSF)

Grant/Contract Number:: R01 AI106307; 0959360; NSF DBI 0922879

OSTI ID:: 1433705

Journal Information:: Journal of Virology, Vol. 92, Issue 8; ISSN 0022-538X

Publisher:: American Society for MicrobiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 6 works

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References (58)

Design of Sequence-Specific DNA Binding Molecules for DNA Methyltransferase Inhibition Kang, JeenJoo S.; Meier, Jordan L.; Dervan, Peter B. Journal of the American Chemical Society, Vol. 136, Issue 9 https://doi.org/10.1021/ja500211z	journal	February 2014
Role of Intermolecular Interactions of Vesicular Stomatitis Virus Nucleoprotein in RNA Encapsidation Zhang, X.; Green, T. J.; Tsao, J. Journal of Virology, Vol. 82, Issue 2 https://doi.org/10.1128/JVI.00935-07	journal	November 2007
Electrostatics of nanosystems: Application to microtubules and the ribosome Baker, N. A.; Sept, D.; Joseph, S. Proceedings of the National Academy of Sciences, Vol. 98, Issue 18, p. 10037-10041 https://doi.org/10.1073/pnas.181342398	journal	August 2001
The Drug Targets and Antiviral Molecules for Treatment of Ebola Virus Infection Wu, Wenjiao; Liu, Shuwen Current Topics in Medicinal Chemistry, Vol. 17, Issue 3 https://doi.org/10.2174/1568026616666160829161318	journal	November 2016
Crystal structures of the transpeptidase domain of the Mycobacterium tuberculosis penicillin-binding protein PonA1 reveal potential mechanisms of antibiotic resistance Filippova, Ekaterina V.; Kieser, Karen J.; Luan, Chi-Hao The FEBS Journal, Vol. 283, Issue 12 https://doi.org/10.1111/febs.13738	journal	May 2016
Insight into the Ebola virus nucleocapsid assembly mechanism: crystal structure of Ebola virus nucleoprotein core domain at 1.8 Å resolution Dong, Shishang; Yang, Peng; Li, Guobang Protein & Cell, Vol. 6, Issue 5 https://doi.org/10.1007/s13238-015-0163-3	journal	April 2015
On the pairing rules for recognition in the minor groove of DNA by pyrrole-imidazole polyamides White, Sarah; Baird, Eldon E.; Dervan, Peter B. Chemistry & Biology, Vol. 4, Issue 8 https://doi.org/10.1016/S1074-5521(97)90243-X	journal	August 1997
Structural basis for G•C recognition in the DNA minor groove Kielkopf, Clara L.; Baird, Eldon E.; Dervan, Peter B. Nature Structural Biology, Vol. 5, Issue 2 https://doi.org/10.1038/nsb0298-104	journal	February 1998
Insight into DNA Minor Groove Unspecific Binding of Pyrrole Polyamide Qiao, Hongwei; Ma, Chunying; Zhang, Xiao Bioconjugate Chemistry, Vol. 26, Issue 10 https://doi.org/10.1021/acs.bioconjchem.5b00309	journal	September 2015
Assembly of the Ebola Virus Nucleoprotein from a Chaperoned VP35 Complex Kirchdoerfer, Robert N.; Abelson, Dafna M.; Li, Sheng Cell Reports, Vol. 12, Issue 1 https://doi.org/10.1016/j.celrep.2015.06.003	journal	July 2015
Crystal Structure of a Nucleocapsid-Like Nucleoprotein-RNA Complex of Respiratory Syncytial Virus Tawar, Rajiv G.; Duquerroy, Stéphane; Vonrhein, Clemens Science, Vol. 326, Issue 5957 https://doi.org/10.1126/science.1177634	journal	November 2009
Improved antiviral activity of a polyamide against high-risk human papillomavirus via N-terminal guanidinium substitution Castaneda, C. H.; Scuderi, M. J.; Edwards, T. G. MedChemComm, Vol. 7, Issue 11 https://doi.org/10.1039/C6MD00371K	journal	January 2016
Antiviral therapy for human rabies Appolinario, Camila M.; Jackson, Alan C. Antiviral Therapy, Vol. 20, Issue 1 https://doi.org/10.3851/IMP2851	journal	January 2014
Crystal Structure of the Rabies Virus Nucleoprotein-RNA Complex Albertini, A. A. V. Science, Vol. 313, Issue 5785 https://doi.org/10.1126/science.1125280	journal	July 2006
HPV episome levels are potently decreased by pyrrole–imidazole polyamides Edwards, Terri G.; Koeller, Kevin J.; Slomczynska, Urszula Antiviral Research, Vol. 91, Issue 2 https://doi.org/10.1016/j.antiviral.2011.05.014	journal	August 2011
Interactions of two large antiviral polyamides with the long control region of HPV16 Vasilieva, Elena; Niederschulte, Jacquelyn; Song, Yang Biochimie, Vol. 127 https://doi.org/10.1016/j.biochi.2016.04.022	journal	August 2016
The nucleocapsid of vesicular stomatitis virus Luo, Ming Science China Life Sciences, Vol. 55, Issue 4 https://doi.org/10.1007/s11427-012-4307-x	journal	April 2012
Structure of the Vesicular Stomatitis Virus Nucleoprotein-RNA Complex Green, T. J. Science, Vol. 313, Issue 5785 https://doi.org/10.1126/science.1126953	journal	July 2006
Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole–imidazole polyamide conjugate Hiraoka, Kiriko; Inoue, Takahiro; Taylor, Rhys Dylan Nature Communications, Vol. 6, Issue 1 https://doi.org/10.1038/ncomms7706	journal	April 2015
DNA Binding Polyamides and the Importance of DNA Recognition in their use as Gene-Specific and Antiviral Agents Koeller, Kevin J. Medicinal Chemistry, Vol. 04, Issue 02 https://doi.org/10.4172/2161-0444.1000162	journal	January 2014
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
UCSF Chimera?A visualization system for exploratory research and analysis Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C. Journal of Computational Chemistry, Vol. 25, Issue 13 https://doi.org/10.1002/jcc.20084	journal	January 2004
What is the antiviral potential of pyrrole-imidazole polyamides? He, Gaofei; Bashkin, James K. Future Medicinal Chemistry, Vol. 7, Issue 15 https://doi.org/10.4155/fmc.15.120	journal	October 2015
Recognition of the Minor Groove of DNA by Hairpin Polyamides Containing α-Substituted-β-Amino Acids Floreancig, Paul E.; Swalley, Susanne E.; Trauger, John W. Journal of the American Chemical Society, Vol. 122, Issue 27 https://doi.org/10.1021/ja000509u	journal	July 2000
Interaction of Vesicular Stomatitis Virus P and N Proteins: Identification of Two Overlapping Domains at the N Terminus of P That Are Involved in N0-P Complex Formation and Encapsidation of Viral Genome RNA Chen, M.; Ogino, T.; Banerjee, A. K. Journal of Virology, Vol. 81, Issue 24 https://doi.org/10.1128/JVI.01244-07	journal	October 2007
Solid Phase Synthesis of Polyamides Containing Imidazole and Pyrrole Amino Acids Baird, Eldon E.; Dervan, Peter B. Journal of the American Chemical Society, Vol. 118, Issue 26 https://doi.org/10.1021/ja960720z	journal	January 1996
Defining GC-specificity in the minor groove: side-by-side binding of the di-imidazole lexitropsin to C-A-T-G-G-C-C-A-T-G Kopka, Mary L.; Goodsell, David S.; Han, Gye Won Structure, Vol. 5, Issue 8 https://doi.org/10.1016/S0969-2126(97)00255-4	journal	August 1997
Influence of a Terminal Formamido Group on the Sequence Recognition of DNA by Polyamides Lacy, Eilyn R.; Le, N. Minh; Price, Carly A. Journal of the American Chemical Society, Vol. 124, Issue 10 https://doi.org/10.1021/ja016154b	journal	March 2002
Modulation of DNA–polyamide interaction by β-alanine substitutions: a study of positional effects on binding affinity, kinetics and thermodynamics Wang, Shuo; Aston, Karl; Koeller, Kevin J. Org. Biomol. Chem., Vol. 12, Issue 38 https://doi.org/10.1039/C4OB01456A	journal	January 2014
A DNA-binding Molecule Targeting the Adaptive Hypoxic Response in Multiple Myeloma Has Potent Antitumor Activity Mysore, V. S.; Szablowski, J.; Dervan, P. B. Molecular Cancer Research, Vol. 14, Issue 3 https://doi.org/10.1158/1541-7786.MCR-15-0361	journal	January 2016
Extended hairpin polyamide motif for sequence-specific recognition in the minor groove of DNA Trauger, John W.; Baird, Eldon E.; Dervan, Peter B. Chemistry & Biology, Vol. 3, Issue 5 https://doi.org/10.1016/S1074-5521(96)90120-9	journal	May 1996
Defining the Epidemiology and Burden of Severe Respiratory Syncytial Virus Infection Among Infants and Children in Western Countries Bont, Louis; Checchia, Paul A.; Fauroux, Brigitte Infectious Diseases and Therapy, Vol. 5, Issue 3 https://doi.org/10.1007/s40121-016-0123-0	journal	August 2016
DNA Damage Repair Genes Controlling Human Papillomavirus (HPV) Episome Levels under Conditions of Stability and Extreme Instability Edwards, Terri G.; Vidmar, Thomas J.; Koeller, Kevin PLoS ONE, Vol. 8, Issue 10 https://doi.org/10.1371/journal.pone.0075406	journal	October 2013
Fluorescence assay of polyamide–DNA interactions Dupureur, Cynthia M.; Bashkin, James K.; Aston, Karl Analytical Biochemistry, Vol. 423, Issue 1 https://doi.org/10.1016/j.ab.2012.01.017	journal	April 2012
Identification of a Broad-Spectrum Inhibitor of Viral RNA Synthesis: Validation of a Prototype Virus-Based Approach Filone, Claire Marie; Hodges, Erin N.; Honeyman, Brian Chemistry & Biology, Vol. 20, Issue 3 https://doi.org/10.1016/j.chembiol.2013.02.011	journal	March 2013
Ebola virus: A gap in drug design and discovery - experimental and computational perspective Balmith, Marissa; Faya, Mbuso; Soliman, Mahmoud E. S. Chemical Biology & Drug Design, Vol. 89, Issue 3 https://doi.org/10.1111/cbdd.12870	journal	October 2016
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
The molecular origin of DNA-drug specificity in netropsin and distamycin. Kopka, M. L.; Yoon, C.; Goodsell, D. Proceedings of the National Academy of Sciences, Vol. 82, Issue 5 https://doi.org/10.1073/pnas.82.5.1376	journal	March 1985
Near-atomic cryo-EM structure of the helical measles virus nucleocapsid Gutsche, I.; Desfosses, A.; Effantin, G. Science, Vol. 348, Issue 6235 https://doi.org/10.1126/science.aaa5137	journal	April 2015
Access to RNA Encapsidated in the Nucleocapsid of Vesicular Stomatitis Virus Green, T. J.; Rowse, M.; Tsao, J. Journal of Virology, Vol. 85, Issue 6 https://doi.org/10.1128/JVI.01927-10	journal	December 2010
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Influence of structural variation on nuclear localization of DNA-binding polyamide-fluorophore conjugates Edelson, B. S. Nucleic Acids Research, Vol. 32, Issue 9 https://doi.org/10.1093/nar/gkh609	journal	May 2004
Methyl group conformation-determining intermolecular C–H...O hydrogen bonds: structure of N -methyl-2-pyrrolidone Müller, G.; Lutz, M.; Harder, S. Acta Crystallographica Section B Structural Science, Vol. 52, Issue 6 https://doi.org/10.1107/S0108768196008300	journal	December 1996
Correlation of Local Effects of DNA Sequence and Position of β-Alanine Inserts with Polyamide–DNA Complex Binding Affinities and Kinetics Wang, Shuo; Nanjunda, Rupesh; Aston, Karl Biochemistry, Vol. 51, Issue 49 https://doi.org/10.1021/bi301327v	journal	November 2012
Promoter scanning of the human COX-2 gene with 8-ring polyamides: Unexpected weakening of polyamide–DNA binding and selectivity by replacing an internal N-Me-pyrrole with β-alanine Bashkin, James K.; Aston, Karl; Ramos, Joseph P. Biochimie, Vol. 95, Issue 2 https://doi.org/10.1016/j.biochi.2012.09.023	journal	February 2013
Binding studies of a large antiviral polyamide to a natural HPV sequence He, Gaofei; Vasilieva, Elena; Harris, George Davis Biochimie, Vol. 102 https://doi.org/10.1016/j.biochi.2014.02.011	journal	July 2014
Binding of a hairpin polyamide in the minor groove of DNA: sequence-specific enthalpic discrimination. Pilch, D. S.; Poklar, N.; Gelfand, C. A. Proceedings of the National Academy of Sciences, Vol. 93, Issue 16 https://doi.org/10.1073/pnas.93.16.8306	journal	August 1996
Extension of Sequence-Specific Recognition in the Minor Groove of DNA by Pyrrole−Imidazole Polyamides to 9−13 Base Pairs Trauger, John W.; Baird, Eldon E.; Mrksich, Milan Journal of the American Chemical Society, Vol. 118, Issue 26 https://doi.org/10.1021/ja960726o	journal	January 1996
Direct Evidence for Methyl Group Coordination by Carbon-Oxygen Hydrogen Bonds in the Lysine Methyltransferase SET7/9 Horowitz, Scott; Yesselman, Joseph D.; Al-Hashimi, Hashim M. Journal of Biological Chemistry, Vol. 286, Issue 21 https://doi.org/10.1074/jbc.M111.232876	journal	March 2011
Replication stress by Py–Im polyamides induces a non-canonical ATR-dependent checkpoint response Martínez, Thomas F.; Phillips, John W.; Karanja, Kenneth K. Nucleic Acids Research, Vol. 42, Issue 18 https://doi.org/10.1093/nar/gku866	journal	September 2014
Study of the Assembly of Vesicular Stomatitis Virus N Protein: Role of the P Protein Green, T. J.; Macpherson, S.; Qiu, S. Journal of Virology, Vol. 74, Issue 20 https://doi.org/10.1128/JVI.74.20.9515-9524.2000	journal	October 2000
Frequent side chain methyl carbon-oxygen hydrogen bonding in proteins revealed by computational and stereochemical analysis of neutron structures: Side Chain Carbon-Oxygen Hydrogen Bonding in Proteins Yesselman, Joseph D.; Horowitz, Scott; Brooks, Charles L. Proteins: Structure, Function, and Bioinformatics, Vol. 83, Issue 3 https://doi.org/10.1002/prot.24724	journal	January 2015
Replication and amplification of novel vesicular stomatitis virus minigenomes encoding viral structural proteins. Stillman, E. A.; Rose, J. K.; Whitt, M. A. Journal of virology, Vol. 69, Issue 5 https://doi.org/10.1128/JVI.69.5.2946-2953.1995	journal	January 1995
Effects of the A·T/T·A Degeneracy of Pyrrole−Imidazole Polyamide Recognition in the Minor Groove of DNA ^† White, Sarah; Baird, Eldon E.; Dervan, Peter B. Biochemistry, Vol. 35, Issue 38 https://doi.org/10.1021/bi960744i	journal	January 1996
Binding site size limit of the 2:1 pyrrole-imidazole polyamide-DNA motif. Kelly, J. J.; Baird, E. E.; Dervan, P. B. Proceedings of the National Academy of Sciences, Vol. 93, Issue 14 https://doi.org/10.1073/pnas.93.14.6981	journal	July 1996
Crystal Structure of the Core Region of Hantavirus Nucleocapsid Protein Reveals the Mechanism for Ribonucleoprotein Complex Formation Guo, Yu; Wang, Wenming; Sun, Yuna Journal of Virology, Vol. 90, Issue 2 https://doi.org/10.1128/JVI.02523-15	journal	November 2015
Single-Amino-Acid Alterations in a Highly Conserved Central Region of Vesicular Stomatitis Virus N Protein Differentially Affect the Viral Nucleocapsid Template Functions Nayak, D.; Panda, D.; Das, S. C. Journal of Virology, Vol. 83, Issue 11 https://doi.org/10.1128/JVI.02289-08	journal	March 2009
Sequence-Specific DNA Recognition by Cyclic Pyrrole-Imidazole Cysteine-Derived Polyamide Dimers Yamamoto, Makoto; Bando, Toshikazu; Morinaga, Hironobu Chemistry - A European Journal, Vol. 20, Issue 3 https://doi.org/10.1002/chem.201302482	journal	December 2013

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Title: A Polyamide Inhibits Replication of Vesicular Stomatitis Virus by Targeting RNA in the Nucleocapsid

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