Voltage-Switchable HCl Transport Enabled by Lipid Headgroup-Transporter Interactions.

Area of Science:

• Supramolecular Chemistry
• Membrane Transport
• Medicinal Chemistry

Background:

• Synthetic anion transporters show anti-cancer potential by neutralizing pH gradients and inhibiting autophagy.
• Existing synthetic transporters exhibit limited proton/chloride (H+/Cl-) symport activity compared to natural products like prodigiosin.
• The precise mechanisms of synthetic anion transporters remain incompletely understood.

Purpose of the Study:

• To engineer a synthetic anion transporter with enhanced H+/Cl- symport activity and novel transport properties.
• To elucidate the mechanism behind voltage-switchable transport and lack of uniport activity.
• To provide mechanistic insights into anion transporter function and develop voltage-switchable artificial membrane systems.

Main Methods:

• Synthesis and characterization of a chloride-selective tetraurea macrocycle.
• Measurement of H+/Cl- symport activity and comparison with prodigiosin.
• Investigation of anion binding affinity and transport mechanisms of related anion transporters.
• Analysis of transporter interaction with phospholipid headgroups and membrane diffusion.

Main Results:

• A novel tetraurea macrocycle achieved record-high H+/Cl- symport activity, comparable to prodigiosin.
• The synthesized macrocycle demonstrated unprecedented voltage-switchable transport properties.
• Lack of uniport activity and voltage-dependent symport were attributed to strong binding to phospholipid headgroups.
• An unusual H+/Cl- symport mechanism involving only charged species was identified.

Conclusions:

• The developed tetraurea macrocycle represents a significant advancement in synthetic anion transporter design.
• The study reveals a novel mechanism for voltage-switchable transport in artificial systems.
• Findings offer critical mechanistic insights into anion transport and potential applications in cancer therapy and biomimetic membranes.