Advanced Molecular Tweezers Effectively Target Membranes Lacking Choline Headgroups for Broad-Spectrum Antiviral...

Area of Science:

• Membrane biophysics
• Virology
• Medicinal chemistry

Background:

• Broad-spectrum antivirals are crucial for combating viral threats.
• Parental molecular tweezers (CLR01, CLR05) disrupt viral envelopes by binding choline headgroups.
• Ester-functionalized "advanced" tweezers exhibit enhanced antiviral potency.

Purpose of the Study:

• To elucidate the molecular basis for the enhanced antiviral activity of advanced molecular tweezers.
• To understand the mechanism of action of advanced tweezers against viral envelopes.

Main Methods:

• Liposome leakage assays
• Giant unilamellar vesicles (GUVs)
• Nuclear Magnetic Resonance (NMR)
• Langmuir film balance experiments
• Atomistic simulations

Main Results:

• Advanced tweezers bind not only choline-containing lipids but also engage lipids lacking choline via hydrophobic insertion.
• These interactions destabilize membranes enriched in sphingomyelin, unsaturated acyl chains, or inverted cone-shaped lipids.
• The mechanism is particularly effective against small, highly curved lipid particles, similar to viral particles.

Conclusions:

• Advanced molecular tweezers possess a dual mechanism of action: choline binding and hydrophobic insertion.
• This dual mechanism underpins their broad-spectrum antiviral activity against enveloped viruses.
• Advanced molecular tweezers represent a promising new class of membrane-targeting antivirals for prophylaxis and therapy.