Advanced molecular tweezers for broad-spectrum antiviral efficiacy
RESOLV member Prof. Elsa Sanchez-Garcia and a group of researchers present, CLR01 and CLR05 based advanced molecular tweezers that 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.
Broad-spectrum antivirals are urgently needed to address current and emerging viral threats. While the molecular tweezers CLR01 and CLR05 disrupt viral envelopes by binding choline headgroups, ester-functionalized “advanced” tweezers show substantially enhanced antiviral potency. Here, the researchers elucidate the molecular origins of this improved activity using liposome leakage assays, giant unilamellar vesicles, NMR spectroscopy, Langmuir film balance experiments, and atomistic simulations. They demonstrate that advanced tweezers not only bind choline-containing lipids but also transiently insert into membranes lacking choline headgroups through conserved hydrophobic interactions. These interactions preferentially destabilize curved, sphingomyelin-rich and unsaturated lipid membranes characteristic of enveloped viruses, revealing a dual mechanism that underlies their broad antiviral efficacy.
