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

Area of Science:

• Virology
• Drug Discovery
• Biochemistry

Background:

• Viruses initiate infection by binding to cell surface glycoproteins like heparan sulfate proteoglycans (HSPG) and sialic acid (SA).
• Broad-spectrum multivalent entry inhibitors (MEI) mimic these moieties but typically exhibit reversible inhibition, limiting their therapeutic efficacy due to concentration-dependent loss.
• Existing HSPG-mimicking MEIs showed only reversible inhibition against SARS-CoV-2.

Purpose of the Study:

• To develop novel MEIs with irreversible inhibition mechanisms for broad-spectrum antiviral activity.
• To identify design principles for creating irreversible MEIs effective against viruses like SARS-CoV-2 and influenza.
• To evaluate the in vivo efficacy of these novel irreversible MEIs.

Main Methods:

• Systematic investigation of small molecules with a core, hydrophobic arms, and HSPG-mimicking moieties.
• Testing inhibition reversibility against various viruses, including SARS-CoV-2.
• In vivo efficacy studies in a Syrian hamster model for SARS-CoV-2 using intranasal and aerosol administration.
• Development and testing of SA-mimicking MEIs.

Main Results:

• Identification of MEIs with irreversible inhibition against a range of viruses, including SARS-CoV-2.
• Demonstration of therapeutic efficacy of irreversible MEIs against SARS-CoV-2 in hamsters via intranasal and aerosol routes 12 hours post-infection.
• Successful application of design rules to create SA-mimicking MEIs with irreversible inhibition against influenza viruses.

Conclusions:

• Hydrophobic arm modification of MEIs can achieve irreversible inhibition, overcoming concentration-dependent efficacy loss.
• The developed irreversible MEIs demonstrate significant therapeutic potential against SARS-CoV-2 and influenza viruses.
• The design principles established are applicable for creating next-generation broad-spectrum antiviral entry inhibitors.