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Biological Chemistry

Synthetic receptors imitate GPCRs

Vesicle signaling system could deliver drugs on command

by Stu Borman
September 21, 2017 | APPEARED IN VOLUME 95, ISSUE 38

Credit: Adapted from JACS
A synthetic GPCR-like system uses hydroxide first messengers (orange) to deprotonate a receptor end group (blue), causing the receptor to move down into the vesicle membrane. The other end group (pink) binds a zinc cofactor (green) to catalyze a reaction that produces a second messenger, a surfactant (yellow), that makes the membrane more permeable and permits cargo release (purple).

G-protein-coupled receptors (GPCRs) are ubiquitous signaling proteins that sit in the membranes of our cells. They’re involved in many physiological processes and, as a result, are frequent drug targets. Researchers now report that a synthetic system that mimics the signaling activity of a GPCR could deliver druglike cargo when triggered by chemical cues.

GPCRs lie in wait in cell membranes until signaling molecules such as hormones bind to the receptors’ external face. These so-called first messengers turn on the GPCR, which then undergoes conformational changes that translate the activation signal to the part of the receptor facing the inside of the cell. That face of the receptor then activates G proteins that pass the signal through second messenger molecules to targets inside the cell, turning on or off enzymes, ion channels, and other cell components.

Last year, Nicholas H. Williams of the University of Sheffield, Christopher A. Hunter of the University of Cambridge, and coworkers designed artificial receptors that mimic GPCRs by transmitting signals from the outside to the inside of membrane-enclosed vesicles (Nat. Chem. 2016, DOI: 10.1038/nchem.2678). They created synthetic receptors—steroid molecules with a protonated morpholine on one end and a pyridine-oxime procatalyst on the other—that embed in lipid bilayer vesicles. Adding hydroxide to the solution outside the vesicle membranes deprotonates the morpholine. This makes the end group less hydrophilic and causes the receptor to move deeper into the hydrophobic membrane. That motion, in turn, allows the receptor’s pyridine-oxime to poke out into the interior of the vesicle. The procatalyst then binds a zinc cofactor, enabling it to accelerate a reaction that produces a fluorescent molecule.

In a new paper, the team demonstrates that this synthetic receptor system can perform a drug delivery-like function, releasing cargo molecules preloaded into the vesicles (J. Am. Chem. Soc. 2017, DOI: 10.1021/jacs.7b07747). In this system, a hydroxide first messenger initiates receptor motion that activates a catalytic hydrolytic reaction inside the vesicle. The reaction converts an encapsulated ester into a surfactant second messenger. The surfactant causes the lipid bilayer to become permeable, allowing the cargo molecules to escape. The interior catalytic activity amplifies the original hydroxide signal, similar to the way GPCRs amplify hormone signaling.

“This paper takes a conceptually original approach to a challenging problem,” mimicking GPCR activity, says molecular systems engineer Stefan Matile of the University of Geneva. It may not be ready for immediate commercialization, “but it’s most inspiring for long-term progress—exactly the type of research we would like to see more of.”

“The paper shows how synthetic systems can be designed to be conceptually equivalent to biological membrane-bound receptors,” says Jonathan Clayden of the University of Bristol, a specialist in molecular communication devices. “It’s remarkable how well they work.”

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