Alkyl chain; American Chemical Society; Antivirals; Broad spectrum; Cell-surface heparan; Heparan sulfate proteoglycans; Hydrophobics; Irreversible inhibitions; Reversible mechanisms; Sialic acids; Chemistry (all); Chemical Engineering (all)
Abstract :
[en] Most viruses start their invasion by binding to glycoproteins’ moieties on the cell surface (heparan sulfate proteoglycans [HSPG] or sialic acid [SA]). Antivirals mimicking these moieties multivalently are known as broad-spectrum multivalent entry inhibitors (MEI). Due to their reversible mechanism, efficacy is lost when concentrations fall below an inhibitory threshold. To overcome this limitation, we modify MEIs with hydrophobic arms rendering the inhibitory mechanism irreversible, i.e., preventing the efficacy loss upon dilution. However, all our HSPG-mimicking MEIs only showed reversible inhibition against HSPG-binding SARS-CoV-2. Here, we present a systematic investigation of a series of small molecules, all containing a core and multiple hydrophobic arms terminated with HSPG-mimicking moieties. We identify the ones that have irreversible inhibition against all viruses including SARS-CoV-2 and discuss their design principles. We show efficacy in vivo against SARS-CoV-2 in a Syrian hamster model through both intranasal instillation and aerosol inhalation in a therapeutic setting (12 h postinfection). We also show the utility of the presented design rules in producing SA-mimicking MEIs with irreversible inhibition against SA-binding influenza viruses.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Zhu, Yong ; Institute of Materials, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Gasbarri, Matteo ; Institute of Materials, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Zebret, Soumaila; Institute of Materials, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Pawar, Sujeet; Institute of Materials, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Mathez, Gregory ; Institute of Microbiology, University Hospital of Lausanne and University of Lausanne, Lausanne, Switzerland
Diderich, Jacob ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH) > FARAH: Santé publique vétérinaire
Valencia-Camargo, Alma Delia; Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland
Russenberger, Doris; Department of Infectious Diseases and Hospital Hygiene, University Hospital Zurich, Zurich, Switzerland
Wang, Heyun ; Institute of Materials, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Silva, Paulo Henrique Jacob; Institute of Materials, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Dela Cruz, Jay-Ar B.; Institute of Materials, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Wei, Lixia; Institute of Materials, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Cagno, Valeria; Institute of Microbiology, University Hospital of Lausanne and University of Lausanne, Lausanne, Switzerland
Münz, Christian; Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland
Speck, Roberto F.; Department of Infectious Diseases and Hospital Hygiene, University Hospital Zurich, Zurich, Switzerland
Desmecht, Daniel ; Université de Liège - ULiège > Département de morphologie et pathologie (DMP) > Pathologie spéciale et autopsies
Stellacci, Francesco ; Institute of Materials, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
WSS - Werner Siemens-Stiftung SNF - Schweizerischer Nationalfonds zur Förderung der wissenschaftlichen Forschung European Union. Marie Skłodowska-Curie Actions
Funding text :
This study has been supported by Werner Siemens-Stiftung, the Swiss National Science Foundation Synergia Grant CRSII5_180323, and the European Union\u2019s Horizon 2020 Research and Innovation Programme under the Marie Sk\u0142odowska\u2013Curie Grant 754354.
Dimitrov, D. S. Virus Entry: Molecular Mechanisms and Biomedical Applications. Nat. Rev. Microbiol. 2004, 2 ( 2), 109- 122, 10.1038/nrmicro817
Viral Entry into Host Cells; Poehlmann, S., Simmons, G., Eds.; Advances in Experimental Medicine and Biology Series, Vol. 790; Springer Science+Business Media and Landes Bioscience: New York, NY and Austin, TX, 2013.
Xu, D.; Esko, J. D. Demystifying Heparan Sulfate-Protein Interactions. Annu. Rev. Biochem. 2014, 83 ( 1), 129- 157, 10.1146/annurev-biochem-060713-035314
Shieh, M. T.; WuDunn, D.; Montgomery, R. I.; Esko, J. D.; Spear, P. G. Cell Surface Receptors for Herpes Simplex Virus Are Heparan Sulfate Proteoglycans. J. Cell Biol. 1992, 116 ( 5), 1273- 1281, 10.1083/jcb.116.5.1273
WuDunn, D.; Spear, P. G. Initial Interaction of Herpes Simplex Virus with Cells Is Binding to Heparan Sulfate. J. Virol. 1989, 63 ( 1), 52- 58, 10.1128/jvi.63.1.52-58.1989
Hao, W.; Ma, B.; Li, Z.; Wang, X.; Gao, X.; Li, Y.; Qin, B.; Shang, S.; Cui, S.; Tan, Z. Binding of the SARS-CoV-2 Spike Protein to Glycans. Sci. Bull. 2021, 66 ( 12), 1205- 1214, 10.1016/j.scib.2021.01.010
Clausen, T. M.; Sandoval, D. R.; Spliid, C. B.; Pihl, J.; Perrett, H. R.; Painter, C. D.; Narayanan, A.; Majowicz, S. A.; Kwong, E. M.; McVicar, R. N.; Thacker, B. E.; Glass, C. A.; Yang, Z.; Torres, J. L.; Golden, G. J.; Bartels, P. L.; Porell, R. N.; Garretson, A. F.; Laubach, L.; Feldman, J.; Yin, X.; Pu, Y.; Hauser, B. M.; Caradonna, T. M.; Kellman, B. P.; Martino, C.; Gordts, P. L. S. M.; Chanda, S. K.; Schmidt, A. G.; Godula, K.; Leibel, S. L.; Jose, J.; Corbett, K. D.; Ward, A. B.; Carlin, A. F.; Esko, J. D. SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2. Cell 2020, 183 ( 4), 1043- 1057, e15 10.1016/j.cell.2020.09.033
Connell, B. J.; Lortat-Jacob, H. Human Immunodeficiency Virus and Heparan Sulfate: From Attachment to Entry Inhibition. Front. Immunol. 2013, 4, n/a, 10.3389/fimmu.2013.00385
Jarousse, N.; Chandran, B.; Coscoy, L. Lack of Heparan Sulfate Expression in B-Cell Lines: Implications for Kaposi’s Sarcoma-Associated Herpesvirus and Murine Gammaherpesvirus 68 Infections. J. Virol. 2008, 82 ( 24), 12591- 12597, 10.1128/JVI.01167-08
Helander, A.; Silvey, K. J.; Mantis, N. J.; Hutchings, A. B.; Chandran, K.; Lucas, W. T.; Nibert, M. L.; Neutra, M. R. The Viral Σ1 Protein and Glycoconjugates Containing Α2-3-Linked Sialic Acid Are Involved in Type 1 Reovirus Adherence to M Cell Apical Surfaces. J. Virol. 2003, 77 ( 14), 7964- 7977, 10.1128/JVI.77.14.7964-7977.2003
Yu, X.; Dang, V. T.; Fleming, F. E.; von Itzstein, M.; Coulson, B. S.; Blanchard, H. Structural Basis of Rotavirus Strain Preference toward N -Acetyl- or N -Glycolylneuraminic Acid-Containing Receptors. J. Virol. 2012, 86 ( 24), 13456- 13466, 10.1128/JVI.06975-11
Haselhorst, T.; Fleming, F. E.; Dyason, J. C.; Hartnell, R. D.; Yu, X.; Holloway, G.; Santegoets, K.; Kiefel, M. J.; Blanchard, H.; Coulson, B. S.; von Itzstein, M. Sialic Acid Dependence in Rotavirus Host Cell Invasion. Nat. Chem. Biol. 2009, 5 ( 2), 91- 93, 10.1038/nchembio.134
Liu, Y.; Sheng, J.; Baggen, J.; Meng, G.; Xiao, C.; Thibaut, H. J.; van Kuppeveld, F. J. M.; Rossmann, M. G. Sialic Acid-Dependent Cell Entry of Human Enterovirus D68. Nat. Commun. 2015, 6 ( 1), 8865, 10.1038/ncomms9865
Lipton, H. L.; Kumar, A. S. M.; Hertzler, S.; Reddi, H. V. Differential Usage of Carbohydrate Co-Receptors Influences Cellular Tropism of Theiler’s Murine Encephalomyelitis Virus Infection of the Central Nervous System. Glycoconj. J. 2006, 23 ( 1-2), 39- 49, 10.1007/s10719-006-5436-x
Nam, H.-J.; Gurda-Whitaker, B.; Gan, W. Y.; Ilaria, S.; McKenna, R.; Mehta, P.; Alvarez, R. A.; Agbandje-McKenna, M. Identification of the Sialic Acid Structures Recognized by Minute Virus of Mice and the Role of Binding Affinity in Virulence Adaptation. J. Biol. Chem. 2006, 281 ( 35), 25670- 25677, 10.1074/jbc.M604421200
Rogers, G. N.; Paulson, J. C. Receptor Determinants of Human and Animal Influenza Virus Isolates: Differences in Receptor Specificity of the H3 Hemagglutinin Based on Species of Origin. Virology 1983, 127 ( 2), 361- 373, 10.1016/0042-6822(83)90150-2
Soria-Martinez, L.; Bauer, S.; Giesler, M.; Schelhaas, S.; Materlik, J.; Janus, K.; Pierzyna, P.; Becker, M.; Snyder, N. L.; Hartmann, L.; Schelhaas, M. Prophylactic Antiviral Activity of Sulfated Glycomimetic Oligomers and Polymers. J. Am. Chem. Soc. 2020, 142 ( 11), 5252- 5265, 10.1021/jacs.9b13484
Nagao, M.; Matsubara, T.; Hoshino, Y.; Sato, T.; Miura, Y. Topological Design of Star Glycopolymers for Controlling the Interaction with the Influenza Virus. Bioconjug. Chem. 2019, 30 ( 4), 1192- 1198, 10.1021/acs.bioconjchem.9b00134
Lundquist, J. J.; Toone, E. J. The Cluster Glycoside Effect. Chem. Rev. 2002, 102 ( 2), 555- 578, 10.1021/cr000418f
Lu, W.; Pieters, R. J. Carbohydrate-Protein Interactions and Multivalency: Implications for the Inhibition of Influenza A Virus Infections. Expert Opin. Drug Discov. 2019, 14 ( 4), 387- 395, 10.1080/17460441.2019.1573813
Anderson, R. A.; Feathergill, K. A.; Diao, X.-H.; Cooper, M. D.; Kirkpatrick, R.; Herold, B. C.; Doncel, G. F.; Chany, C. J.; Waller, D. P.; Rencher, W. F.; Zaneveld, L. J. D. Preclinical Evaluation of Sodium Cellulose Sulfate (Ushercell) as a Contraceptive Antimicrobial Agent. J. Androl. 2002, 23 ( 3), 426- 438, 10.1002/j.1939-4640.2002.tb02250.x
Lee, C. Carrageenans as Broad-Spectrum Microbicides: Current Status and Challenges. Mar. Drugs 2020, 18 ( 9), 435, 10.3390/md18090435
Cheshenko, N.; Keller, M. J.; MasCasullo, V.; Jarvis, G. A.; Cheng, H.; John, M.; Li, J.-H.; Hogarty, K.; Anderson, R. A.; Waller, D. P.; Zaneveld, L. J. D.; Profy, A. T.; Klotman, M. E.; Herold, B. C. Candidate Topical Microbicides Bind Herpes Simplex Virus Glycoprotein B and Prevent Viral Entry and Cell-to-Cell Spread. Antimicrob. Agents Chemother. 2004, 48 ( 6), 2025- 2036, 10.1128/AAC.48.6.2025-2036.2004
Donskyi, I. S.; Azab, W.; Cuellar-Camacho, J. L.; Guday, G.; Lippitz, A.; Unger, W. E. S.; Osterrieder, K.; Adeli, M.; Haag, R. Functionalized Nanographene Sheets with High Antiviral Activity through Synergistic Electrostatic and Hydrophobic Interactions. Nanoscale 2019, 11 ( 34), 15804- 15809, 10.1039/C9NR05273A
Pirrone, V.; Wigdahl, B.; Krebs, F. C. The Rise and Fall of Polyanionic Inhibitors of the Human Immunodeficiency Virus Type 1. Antiviral Res. 2011, 90 ( 3), 168- 182, 10.1016/j.antiviral.2011.03.176
Lu, W.; Du, W.; Somovilla, V. J.; Yu, G.; Haksar, D.; de Vries, E.; Boons, G.-J.; de Vries, R. P.; de Haan, C. A. M.; Pieters, R. J. Enhanced Inhibition of Influenza A Virus Adhesion by Di- and Trivalent Hemagglutinin Inhibitors. J. Med. Chem. 2019, 62 ( 13), 6398- 6404, 10.1021/acs.jmedchem.9b00303
Kwon, S.-J.; Na, D. H.; Kwak, J. H.; Douaisi, M.; Zhang, F.; Park, E. J.; Park, J.-H.; Youn, H.; Song, C.-S.; Kane, R. S.; Dordick, J. S.; Lee, K. B.; Linhardt, R. J. Nanostructured Glycan Architecture Is Important in the Inhibition of Influenza A Virus Infection. Nat. Nanotechnol. 2017, 12 ( 1), 48- 54, 10.1038/nnano.2016.181
Cagno, V.; Andreozzi, P.; D’Alicarnasso, M.; Jacob Silva, P.; Mueller, M.; Galloux, M.; Le Goffic, R.; Jones, S. T.; Vallino, M.; Hodek, J.; Weber, J.; Sen, S.; Janeček, E.-R.; Bekdemir, A.; Sanavio, B.; Martinelli, C.; Donalisio, M.; Rameix Welti, M.-A.; Eleouet, J.-F.; Han, Y.; Kaiser, L.; Vukovic, L.; Tapparel, C.; Král, P.; Krol, S.; Lembo, D.; Stellacci, F. Broad-Spectrum Non-Toxic Antiviral Nanoparticles with a Virucidal Inhibition Mechanism. Nat. Mater. 2018, 17 ( 2), 195- 203, 10.1038/nmat5053
Jones, S. T.; Cagno, V.; Janeček, M.; Ortiz, D.; Gasilova, N.; Piret, J.; Gasbarri, M.; Constant, D. A.; Han, Y.; Vuković, L.; Král, P.; Kaiser, L.; Huang, S.; Constant, S.; Kirkegaard, K.; Boivin, G.; Stellacci, F.; Tapparel, C. Modified Cyclodextrins as Broad-Spectrum Antivirals. Sci. Adv. 2020, 6 ( 5), eaax9318 10.1126/sciadv.aax9318
Mohammadifar, E.; Gasbarri, M.; Cagno, V.; Achazi, K.; Tapparel, C.; Haag, R.; Stellacci, F. Polyanionic Amphiphilic Dendritic Polyglycerols as Broad-Spectrum Viral Inhibitors with a Virucidal Mechanism. Biomacromolecules 2022, 23 ( 3), 983- 991, 10.1021/acs.biomac.1c01376
Kocabiyik, O.; Cagno, V.; Silva, P. J.; Zhu, Y.; Sedano, L.; Bhide, Y.; Mettier, J.; Medaglia, C.; Da Costa, B.; Constant, S.; Huang, S.; Kaiser, L.; Hinrichs, W. L. J.; Huckriede, A.; Le Goffic, R.; Tapparel, C.; Stellacci, F. Non-Toxic Virucidal Macromolecules Show High Efficacy Against Influenza Virus Ex Vivo and In Vivo. Adv. Sci. 2021, 8 ( 3), 2001012, 10.1002/advs.202001012
Baram-Pinto, D.; Shukla, S.; Gedanken, A.; Sarid, R. Inhibition of HSV-1 Attachment, Entry, and Cell-to-Cell Spread by Functionalized Multivalent Gold Nanoparticles. Small 2010, 6 ( 9), 1044- 1050, 10.1002/smll.200902384
Vaheri, A. Heparin and Related Polyionic Substances as Virus Inhibitors. Acta Pathol. Microbiol. Scand. Suppl. 1964, Suppl. 171, 1- 98
Sametband, M.; Shukla, S.; Meningher, T.; Hirsh, S.; Mendelson, E.; Sarid, R.; Gedanken, A.; Mandelboim, M. Effective Multi-Strain Inhibition of Influenza Virus by Anionic Gold Nanoparticles. MedChemComm 2011, 2 ( 5), 421, 10.1039/c0md00229a
Gasbarri, M.; V’kovski, P.; Torriani, G.; Thiel, V.; Stellacci, F.; Tapparel, C.; Cagno, V. SARS-CoV-2 Inhibition by Sulfonated Compounds. Microorganisms 2020, 8 ( 12), 1894, 10.3390/microorganisms8121894
Zhu, Y.; Sysoev, A. A.; Silva, P. H. J.; Batista, M.; Stellacci, F. Antiviral Mechanism of Virucidal Sialic Acid Modified Cyclodextrin. Pharmaceutics 2023, 15 ( 2), 582, 10.3390/pharmaceutics15020582
Chesnokova, L. S.; Valencia, S. M.; Hutt-Fletcher, L. M. The BDLF3 Gene Product of Epstein-Barr Virus, Gp150, Mediates Non-Productive Binding to Heparan Sulfate on Epithelial Cells and Only the Binding Domain of CD21 Is Required for Infection. Virology 2016, 494, 23- 28, 10.1016/j.virol.2016.04.002
Stevens, J.; Blixt, O.; Paulson, J. C.; Wilson, I. A. Glycan Microarray Technologies: Tools to Survey Host Specificity of Influenza Viruses. Nat. Rev. Microbiol. 2006, 4 ( 11), 857- 864, 10.1038/nrmicro1530
Leibbrandt, A.; Meier, C.; König-Schuster, M.; Weinmüllner, R.; Kalthoff, D.; Pflugfelder, B.; Graf, P.; Frank-Gehrke, B.; Beer, M.; Fazekas, T.; Unger, H.; Prieschl-Grassauer, E.; Grassauer, A. Iota-Carrageenan Is a Potent Inhibitor of Influenza A Virus Infection. PLoS ONE 2010, 5 ( 12), e14320 10.1371/journal.pone.0014320
Abdelnabi, R.; Foo, C. S.; Jochmans, D.; Vangeel, L.; De Jonghe, S.; Augustijns, P.; Mols, R.; Weynand, B.; Wattanakul, T.; Hoglund, R. M.; Tarning, J.; Mowbray, C. E.; Sjö, P.; Escudié, F.; Scandale, I.; Chatelain, E.; Neyts, J. The Oral Protease Inhibitor (PF-07321332) Protects Syrian Hamsters against Infection with SARS-CoV-2 Variants of Concern. Nat. Commun. 2022, 13 ( 1), 719, 10.1038/s41467-022-28354-0
Owen, D. R.; Allerton, C. M. N.; Anderson, A. S.; Aschenbrenner, L.; Avery, M.; Berritt, S.; Boras, B.; Cardin, R. D.; Carlo, A.; Coffman, K. J.; Dantonio, A.; Di, L.; Eng, H.; Ferre, R.; Gajiwala, K. S.; Gibson, S. A.; Greasley, S. E.; Hurst, B. L.; Kadar, E. P.; Kalgutkar, A. S.; Lee, J. C.; Lee, J.; Liu, W.; Mason, S. W.; Noell, S.; Novak, J. J.; Obach, R. S.; Ogilvie, K.; Patel, N. C.; Pettersson, M.; Rai, D. K.; Reese, M. R.; Sammons, M. F.; Sathish, J. G.; Singh, R. S. P.; Steppan, C. M.; Stewart, A. E.; Tuttle, J. B.; Updyke, L.; Verhoest, P. R.; Wei, L.; Yang, Q.; Zhu, Y. An Oral SARS-CoV-2 M pro Inhibitor Clinical Candidate for the Treatment of COVID-19. Science 2021, 374 ( 6575), 1586- 1593, 10.1126/science.abl4784
Li, J.; Wang, Y.; Solanki, K.; Atre, R.; Lavrijsen, M.; Pan, Q.; Baig, M. S.; Li, P. Nirmatrelvir Exerts Distinct Antiviral Potency against Different Human Coronaviruses. Antiviral Res. 2023, 211, 105555, 10.1016/j.antiviral.2023.105555
Xu, R.; McBride, R.; Nycholat, C. M.; Paulson, J. C.; Wilson, I. A. Structural Characterization of the Hemagglutinin Receptor Specificity from the 2009 H1N1 Influenza Pandemic. J. Virol. 2012, 86 ( 2), 982- 990, 10.1128/JVI.06322-11
