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  4. Benzene with Alkyl Chains Is a Universal Scaffold for Multivalent Virucidal Antivirals
 
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research article

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

Zhu, Yong  
•
Gasbarri, Matteo  
•
Zebret, Soumaila
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April 4, 2024
Acs Central Science

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.

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Type
research article
DOI
10.1021/acscentsci.4c00054
Web of Science ID

WOS:001197316000001

Author(s)
Zhu, Yong  
•
Gasbarri, Matteo  
•
Zebret, Soumaila
•
Pawar, Sujeet  
•
Mathez, Gregory
•
Diderich, Jacob
•
Valencia-Camargo, Alma Delia
•
Russenberger, Doris
•
Wang, Heyun  
•
Silva, Paulo Henrique Jacob  
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Date Issued

2024-04-04

Publisher

Amer Chemical Soc

Published in
Acs Central Science
Subjects

Physical Sciences

•

Herpes-Simplex-Virus

•

Heparan-Sulfate

•

Sialic-Acid

•

Receptor Specificity

•

Inhibition

•

Binding

•

Protein

•

Entry

•

Cells

Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
SUNMIL  
FunderGrant Number

H2020 Marie Sklodowska-Curie Actions

Werner Siemens-Stiftung

CRSII5_180323

Swiss National Science Foundation Synergia Grant

754354

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Available on Infoscience
April 17, 2024
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/207361
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