Benzene with Alkyl Chains Is a Universal Scaffold for Multivalent Virucidal Antivirals

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,...

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Bibliographic Details
Published in:ACS central science 2024-05, Vol.10 (5), p.1012-1021
Main Authors: Zhu, Yong, Gasbarri, Matteo, Zebret, Soumaila, Pawar, Sujeet, Mathez, Gregory, Diderich, Jacob, Valencia-Camargo, Alma Delia, Russenberger, Doris, Wang, Heyun, Silva, Paulo Henrique Jacob, Dela Cruz, Jay-ar B., Wei, Lixia, Cagno, Valeria, Münz, Christian, Speck, Roberto F., Desmecht, Daniel, Stellacci, Francesco
Format: Article
Language:English
Subjects:
Acids
Antiviral agents
Antiviral drugs
Benzene
Binding
Carbohydrates
Cell surface
COVID-19
Dilution
Effectiveness
Glycoproteins
Heparan sulfate
Heparan sulfate proteoglycans
Herpes viruses
HIV
Human immunodeficiency virus
Hydrocarbons
Hydrophobicity
Influenza
Inhalation
Ligands
Mimicry
Nanoparticles
Proteins
Proteoglycans
Respiration
Severe acute respiratory syndrome coronavirus 2
Toxicity
Viruses
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Summary: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.
ISSN:2374-7943
2374-7951
DOI:10.1021/acscentsci.4c00054