Structure-based driven synthesis and biological evaluation provide innovative novel covalent-allosteric Akt inhibitors.

Trypanosomal and leishmanial infections claim tens of thousands of lives eachy ear.T he metabolism of these unicellular eukaryotic parasites differs from the human host and their enzymes thus constitute promising drug targets. Tryparedoxin (Tpx) from Trypanosoma brucei is the essential oxidoreductase in the parasitesh ydroperoxide-clearance cascade.I nvitro and in vivo functional assays show that as mall, selective inhibitor efficiently inhibits Tpx. With X-rayc rystallography,S AXS,a nalytical SEC,S EC-MALS,M Ds imulations,I TC,a nd NMR spectroscopy, we show howc ovalent binding of this monofunctional inhibitor leads to Tpx dimerization. Intra-and intermolecular inhibitor-inhibitor,p rotein-protein, and inhibitor-protein interactions stabilizet he dimer.T he behavior of this efficient antitrypanosomal molecule thus constitutes an exquisite example of chemically induced dimerization with as mall, monovalent ligand that can be exploited for future drug design.