Dengue virus (DENV) causes 390 million infections per year. Infections can be asymptomatic or range from mild fever to severe haemorrhagic fever and shock syndrome. Currently, no effective antivirals or safe universal vaccine is available. In the present work we tested different gold nanoparticles (AuNP) coated with ligands ω-terminated with sugars bearing multiple sulfonate groups. We aimed to identify compounds with antiviral properties due to irreversible (virucidal) rather than reversible (virustatic) inhibition. The ligands varied in length, in number of sulfonated groups as well as their spatial orientation induced by the sugar head groups. We identified two candidates, a glucose- and a lactose-based ligand showing a low EC50 (effective concentration that inhibit 50% of the viral activity) for DENV-2 inhibition, moderate toxicity and a virucidal effect in hepatocytes with titre reduction of Median Tissue Culture Infectious Dose log10TCID50 2.5 and 3.1. Molecular docking simulations complemented the experimental findings suggesting a molecular rationale behind the binding between sulfonated head groups and DENV-2 envelope protein.

Department of Biological and Environmental Sciences and Technologies University of Salento Lecce Italy

Department of Chemistry University of Bari Aldo Moro Bari Italy

Department of Pharmacy Pharmaceutical Sciences University of Bari Aldo Moro Bari Italy

Institute for Physical and Chemical Processes CNR SS Bari Bari Italy

Institute of Materials Ecole Polytechnique Fédérale de Lausanne Lausanne Switzerland

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Prague Czech Republic

Interfaculty Bioengineering Institute Ecole Polytechnique Fédérale de Lausanne Lausanne Switzerland

Istituto di Cristallografia Consiglio Nazionale delle Ricerche Bari Italy

Laboratory for nanotechnology IRCCS Istituto Tumori Giovanni Paolo 2 Bari Italy

Laboratory for personalized medicine IRCCS Ospedale Specializzato in Gastroenterologia Saverio de Bellis Castellana Grotte BA Italy

ProChimia Surfaces Sp z o o Sopot Poland

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Gould E, Solomon T. Pathogenic flaviviruses. Lancet. 2008;371:500–509. PubMed

Bhatt S, et al. The global distribution and burden of dengue. Nature. 2013;496:504–507. PubMed PMC

Brady OJ, et al. Refining the Global Spatial Limits of Dengue Virus Transmission by Evidence-Based Consensus. PLoS Negl. Trop. Dis. 2012;6:e1760. PubMed PMC

Lim SP. Dengue drug discovery: Progress, challenges and outlook. Antiviral Res. 2019;163:156–178. PubMed

Stanaway JD, et al. The global burden of dengue: an analysis from the Global Burden of Disease Study 2013. Lancet Infect. Dis. 2016;16:712–723. PubMed PMC

Behnam MA, Graf D, Bartenschlager R, Zlotos DP, Klein CD. Discovery of Nanomolar Dengue and West Nile Virus Protease Inhibitors Containing a 4-Benzyloxyphenylglycine Residue. J Med Chem. 2015;58:9354–9370. PubMed

Yin Z, et al. Peptide inhibitors of Dengue virus NS3 protease. Part 1: Warhead. Bioorg Med Chem Lett. 2006;16:36–39. PubMed

Pambudi S, et al. A small compound targeting the interaction between nonstructural proteins 2B and 3 inhibits dengue virus replication. Biochem Biophys Res Commun. 2013;440:393–398. PubMed

Chatelain G, et al. In search of flavivirus inhibitors: evaluation of different tritylated nucleoside analogues. Eur J Med Chem. 2013;65:249–255. PubMed

Saudi M, et al. In search of Flavivirus inhibitors part 2: tritylated, diphenylmethylated and other alkylated nucleoside analogues. Eur J Med Chem. 2014;76:98–109. PubMed

Yin Z, et al. N-sulfonylanthranilic acid derivatives as allosteric inhibitors of dengue viral RNA-dependent RNA polymerase. J Med Chem. 2009;52:7934–7937. PubMed

Yin Z, et al. An adenosine nucleoside inhibitor of dengue virus. Proc Natl Acad Sci USA. 2009;106:20435–20439. PubMed PMC

Nguyen NM, et al. A randomized, double-blind placebo controlled trial of balapiravir, a polymerase inhibitor, in adult dengue patients. J Infect Dis. 2013;207:1442–1450. PubMed PMC

Malet H, et al. The flavivirus polymerase as a target for drug discovery. Antivir. Res. 2008;80:23–35. PubMed

Yap TL, et al. Crystal structure of the dengue virus RNA-dependent RNA polymerase catalytic domain at 1.85-angstrom resolution. J Virol. 2007;81:4753–4765. PubMed PMC

Tichy M, et al. Synthesis and biological activity of benzo-fused 7-deazaadenosine analogues. 5- and 6-substituted 4-amino- or 4-alkylpyrimido[4,5-b]indole ribonucleosides. Bioorg Med Chem. 2013;21:5362–5372. PubMed

Niyomrattanakit P, et al. Inhibition of dengue virus polymerase by blocking of the RNA tunnel. J Virol. 2010;84:5678–5686. PubMed PMC

Lim SP, et al. Potent Allosteric Dengue Virus NS5 Polymerase Inhibitors: Mechanism of Action and Resistance Profiling. PLOS Pathog. 2016;12:e1005737. PubMed PMC

Abdullah, A. A. et al. Discovery of Dengue Virus Inhibitors. Curr. Med. Chem. 26 (2018). PubMed

Wang QY, et al. A small-molecule dengue virus entry inhibitor. Antimicrob Agents Chemother. 2009;53:1823–1831. PubMed PMC

Schmidt AG, Yang PL, Harrison SC. Peptide inhibitors of dengue-virus entry target a late-stage fusion intermediate. PLoS Pathog. 2010;6:e1000851. PubMed PMC

Rai M, et al. Metal nanoparticles: The protective nanoshield against virus infection. Crit. Rev. Microbiol. 2016;42:46–56. PubMed

Ooi ET, Ganesananthan S, Anil R, Kwok FY, Sinniah M. Gastrointestinal manifestations of dengue infection in adults. Med. J. Malaysia. 2008;63:401–5. PubMed

Hodek J, et al. Protective hybrid coating containing silver, copper and zinc cations effective against human immunodeficiency virus and other enveloped viruses. BMC Microbiol. 2016;16(Suppl 1):56. PubMed PMC

Sujitha V, et al. Green-synthesized silver nanoparticles as a novel control tool against dengue virus (DEN-2) and its primary vector Aedes aegypti. Parasitol Res. 2015;114:3315–3325. PubMed

Murugan K, et al. Nanoparticles in the fight against mosquito-borne diseases: bioactivity of Bruguiera cylindrica-synthesized nanoparticles against dengue virus DEN-2 (in vitro) and its mosquito vector Aedes aegypti (Diptera: Culicidae) Parasitol Res. 2015;114:4349–4361. PubMed

Cagno V, et al. Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism. Nat. Mater. 2018;17:195–203. PubMed

Dey P, et al. Multivalent Flexible Nanogels Exhibit Broad-Spectrum Antiviral Activity by Blocking Virus Entry. ACS Nano. 2018;12:6429–6442. PubMed

Green S, Rothman A. Immunopathological mechanisms in dengue and dengue hemorrhagic fever. Curr. Opin. Infect. Dis. 2006;19:429–436. PubMed

Hilgard P. Heparan Sulfate Proteoglycans Initiate Dengue Virus Infection of Hepatocytes. Hepatology. 2000;32:1069–1077. PubMed

Jadav SS, et al. Design, synthesis, optimization and antiviral activity of a class of hybrid dengue virus E protein inhibitors. Bioorg. Med. Chem. Lett. 2015;25:1747–1752. PubMed

Dighe SN, et al. Recent update on anti-dengue drug discovery. Eur. J. Med. Chem. 2019;176:431–455. PubMed

Modis Y, Ogata S, Clements D, Harrison SC. A ligand-binding pocket in the dengue virus envelope glycoprotein. Proc. Natl. Acad. Sci. 2003;100:6986–6991. PubMed PMC

Smith HA, Doughty G, Gorin G. Mercaptan—Disulfide Interchange Reactions. 1 III. Reaction of Cysteine with 4,4’-Dithiobis(benzenesulfonic acid) J. Org. Chem. 1964;29:1484–1488.

Zheng N, Fan J, Stucky GD. One-Step One-Phase Synthesis of Monodisperse Noble-Metallic Nanoparticles and Their Colloidal Crystals. J. Am. Chem. Soc. 2006;128:6550–6551. PubMed

Verma A, et al. Surface-structure-regulated cell-membrane penetration by monolayer-protected nanoparticles. Nat. Mater. 2008;7:588–595. PubMed PMC

Kuna JJ, et al. The effect of nanometre-scale structure on interfacial energy. Nat. Mater. 2009;8:837–842. PubMed

Van Lehn RC, et al. Effect of particle diameter and surface composition on the spontaneous fusion of monolayer-protected gold nanoparticles with lipid bilayers. Nano Lett. 2013;13:4060–7. PubMed PMC

Ni Y, et al. Hepatitis B and D Viruses Exploit Sodium Taurocholate Co-transporting Polypeptide for Species-Specific Entry into Hepatocytes. Gastroenterology. 2014;146:1070–1083.e6. PubMed

Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat. Methods. 2012;9:671–675. PubMed PMC

Reed LJJ, Muench H. A simple method of estimating fifty percent endpoints. Am. J. Hyg. 1938;27:493–497.

Jones G, Willett P, Glen RC, Leach AR, Taylor R. Development and validation of a genetic algorithm for flexible docking 1 1Edited by F. E. Cohen. J. Mol. Biol. 1997;267:727–748. PubMed

Feher M, Williams CI. Effect of Input Differences on the Results of Docking Calculations. J. Chem. Inf. Model. 2009;49:1704–1714. PubMed