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

## TL;DR

New molecular tweezers can target virus membranes without choline, offering broad antiviral effects against many viruses.

## Contribution

The study reveals a dual mechanism of molecular tweezers involving choline binding and hydrophobic insertion for antiviral activity.

## Key findings

- Advanced tweezers destabilize membranes with sphingomyelin or inverted cone-shaped lipids.
- They effectively target small, curved viral-like particles through hydrophobic insertion.
- The dual mechanism explains broad antiviral activity against enveloped viruses.

## Abstract

Broad-spectrum antivirals
are urgently required to counter present
and emerging viral threats. It has previously been shown that the
parental molecular tweezers CLR01 and CLR05 disrupt viral envelopes
by complexing choline headgroups and that ester-functionalized “advanced”
tweezers display markedly enhanced antiviral potency. Here, we determine
the molecular basis of this improved activity. Using liposome leakage
assays, giant unilamellar vesicles, NMR, Langmuir film balance experiments,
and atomistic simulations, we demonstrate that advanced tweezers not
only encapsulate choline-containing lipids but also engage lipids
lacking choline headgroups via transient and conserved hydrophobic
insertion events. These interactions preferentially destabilize membranes
enriched in sphingomyelin, unsaturated acyl chains, or inverted cone-shaped
lipids and are especially effective against small, highly curved particles
resembling viral particles, explaining their broad antiviral activity
for enveloped viruses. Our findings reveal a dual mechanism of action,
choline binding and hydrophobic insertion, that underpins the broad-spectrum
antiviral activity of advanced molecular tweezers and establish them
as a promising new class of membrane-targeting antivirals for prophylactic
and therapeutic use.