2:22 PM
Jun 15, 2017
 |  BC Innovations  |  Tools & Techniques

Clearing chemistry

A new use of click chemistry in vivo can trigger rapid drug clearance

A new study has discovered an in vivo use of click chemistry that can rapidly clear drugs from circulation in case of emergency. Although it raises the possibility of a universal safety switch, its adoption by industry could be limited by the need to individually vet each chemical reactant, plus the product they create.

While click chemistry is a well-established tool for non-toxic labeling of biological molecules in research labs, the method has started to gain traction in drug development as well.

The reactions are attractive because they are "bioorthogonal," which means they can take place inside living systems without having any effect on endogenous biochemical processes. The reason is that the reactants have high selectivity for each other, but are biologically inert.

Jutta Wanner, VP of research at drug delivery company BlinkBio Inc., told BioCentury in vitro bioorthogonal reactions have been key for manufacturing conjugated biologics without disrupting the biochemistry of their protein components. The company is using the strategy to create tunable linkers that couple therapeutic payloads to targeting constructs, based on Fab fragments, which release the payloads in the low pH environment of a tumor.

At least two companies, Shasqi Inc. and Tagworks Pharmaceuticals B.V., are developing in vivo bioorthogonal chemistry platforms to deliver therapeutic compounds with precise spatial and temporal control. The idea is that by caging a drug with one bioorthogonal reactant, it becomes an inactive prodrug until it encounters the second reactant, which is localized to the disease site. The result is a tissue-specific reaction that releases active compound only where it's needed.

Last month in Nature Communications, a team from University of Strasbourg presented the reverse approach. The group used a bioorthogonal reaction -- described as "click and clear" -- to neutralize a modified version of warfarin in vivo and rapidly remove it from circulation.

Although the approach provides a way to counteract warfarin's bleeding risk, study author Alain Wagner told BioCentury the method is versatile and can be applied to a wide range of molecules.

"We designed the experiments to show we could do chemical transformation directly in the living organism. The anti-coagulant drug is an example of what you can do, but it's just one application among others," he said.

He said his team is building a library of bioorthogonal reactants that can be used to either clear or inactivate a wide range of drugs and metabolites. Wagner is research director at Centre National de la Recherche Scientifique (CNRS) in the Laboratory of Biofunctional Chemistry at University of Strasbourg.

"The future is to extend this to other types of exogenous and endogenous compounds," said co-author Wojciech Krezel, a research director at Institut National de la Santé et de la Recherche Médicale (INSERM) in the Institute of Genetics and Molecular and Cellular Biology (IGMBC).

The team has...

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