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

Autor:	Zhu Y; Institute of Materials, École Polytechnique Fédérale de Lausanne, Station 12, 1015 Lausanne, Switzerland., Gasbarri M; Institute of Materials, École Polytechnique Fédérale de Lausanne, Station 12, 1015 Lausanne, Switzerland., Zebret S; Institute of Materials, École Polytechnique Fédérale de Lausanne, Station 12, 1015 Lausanne, Switzerland., Pawar S; Institute of Materials, École Polytechnique Fédérale de Lausanne, Station 12, 1015 Lausanne, Switzerland., Mathez G; Institute of Microbiology, University Hospital of Lausanne and University of Lausanne, Rue du Bugnon 48, 1011 Lausanne, Switerland., Diderich J; Faculty of Veterinary Medicine Department of Pathology, University of Liège, Sart Tilman B43a, 4000 Liège, Belgium., Valencia-Camargo AD; Institute of Experimental Immunology, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland., Russenberger D; Department of Infectious Diseases and Hospital Hygiene, University Hospital Zurich, University of Zurich Rämistrasse 100, 8091 Zurich, Switzerland., Wang H; Institute of Materials, École Polytechnique Fédérale de Lausanne, Station 12, 1015 Lausanne, Switzerland., Silva PHJ; Institute of Materials, École Polytechnique Fédérale de Lausanne, Station 12, 1015 Lausanne, Switzerland., Dela Cruz JB; Institute of Materials, École Polytechnique Fédérale de Lausanne, Station 12, 1015 Lausanne, Switzerland., Wei L; Institute of Materials, École Polytechnique Fédérale de Lausanne, Station 12, 1015 Lausanne, Switzerland., Cagno V; Institute of Microbiology, University Hospital of Lausanne and University of Lausanne, Rue du Bugnon 48, 1011 Lausanne, Switerland., Münz C; Institute of Experimental Immunology, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland., Speck RF; Department of Infectious Diseases and Hospital Hygiene, University Hospital Zurich, University of Zurich Rämistrasse 100, 8091 Zurich, Switzerland., Desmecht D; Faculty of Veterinary Medicine Department of Pathology, University of Liège, Sart Tilman B43a, 4000 Liège, Belgium., Stellacci F; Institute of Materials, École Polytechnique Fédérale de Lausanne, Station 12, 1015 Lausanne, Switzerland.
Jazyk:	angličtina
Zdroj:	ACS central science [ACS Cent Sci] 2024 Apr 04; Vol. 10 (5), pp. 1012-1021. Date of Electronic Publication: 2024 Apr 04 (Print Publication: 2024).
DOI:	10.1021/acscentsci.4c00054
Abstrakt:	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. Competing Interests: The authors declare the following competing financial interest(s): Y.Z., F.S., and M.G. are inventors of the patent Virucidal Compounds, Compositions and Uses Thereof. F.S. and P.J.S. are co-founders of a start-up company, Asterivir, that is developing similar antiviral molecules. (© 2024 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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