A critical step in pharmaceutical discovery is validating the link between target and disease phenotype. The selective inhibition of protein activity can provide such validation but requires specificity and doseability. A 'magic bullet' drug is highly specific for its intended cell-structural target. To combine high specificity and doseability we have utilized a method for incorporation of p-azidophenylalanine (Azf) into domains of target proteins. Strain promoted azide-alkyne cycloaddition is used to covalently attach a bulky moiety to Azf in a protein to disrupt its function. We chose to incorporate Azf into the active site of E. coli aminoacyl transferase, an essential part of the N-end pathway, as a proof of principal system. Azf containing transferase exhibits dose-dependent inhibition upon incubation with a dibenzylcyclooctyne. We are currently assessing the generality of the Azf-dibenzylcyclooctyne 'magic bullet' methodology to target E. coli biological pathways in vivo.

"Magic Bullet" protein inhibition using click chemistry

244th National Meeting (2012)

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