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, 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

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© 2024 The Authors. Published by American Chemical Society.

Déclaration de conflit d'intérêts

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.