Chemoenzymatic Synthesis Of Neuroexcitatory And Cuaac-Compatible Kainoid Aalogs

Background

Kainate receptors, also known as kainic acid receptors are ionotropic receptors that bind to and are responsive to glutamate in neurons. These were originally identified as being activated by the compund kainic acid, orignally isolated from algae. Postsynaptic kainate receptors are involved in excitatory neurotransmission while presynaptic kainate receptors are involved in inhibitory neurotransmission. Kainic acid is a potentially very useful compound but very difficult to synthesize. As a result, there are very few pharmacological tool compounds to study kainate receptors and none that are readily tunable to install labeling compounds. 

Technology Description

Researchers in Shaun McKinnie's lab at UC Santa Cruz have developed a chemoenzymatic route to produce not only kainic acid, but also "clickable" kainic acid derivatives to which fluorescent and other labels can be readily attached. 

 First, an organic synthesis of a kainoid synthase substrate with an alkyne handle is performed. 

 Then the RadC1 enzyme from the red algae Chondria armata cyclizes prealkynic acid into alkynic acid

Then further optimization and scale up yields a kainoid ring and a β-hydroxylated side product

 With this structure, Copper catalyzed azide-alkyne cycloaddition (CuAAC) or "click" chemistry allows rapid diversification from the alkynic scaffold and in vivo functionalization with bioorthogonal handles. 

Applications

• Tool compound for study of kainoid receptor 
• Drug development for new kainoid receptor agonists 
• High throughput screening of new candidate kainoid receptor agonists 

Advantages

• Facile synthesis 
• Addition of labels by click chemistry 
• Labels don't affaect kainic acid binding

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