The Exciting Story of Covalent Reversible Inhibition of Rhodesain, a Key Player in African Sleeping Sickness

webinar

Tue, 16 Nov 2021, 15:00 CET (Berlin)

Prof. Dr. Tanja Schirmeister, University of Mainz; Prof. Dr. Bernd Engels, University of Würzburg; Dr. Christian Kersten, University of Mainz; Natalie Fuchs, University of Mainz

The Exciting Story of Covalent Reversible Inhibition of Rhodesain, a Key Player in African Sleeping Sickness

Human African Trypanosomiasis (HAT, African Sleeping Sickness) is a fatal, neglected tropical disease caused by the parasites Trypanosoma brucei. Most available drugs for treatment of the disease lack efficiency and have severe side effects. α-halovinylsulfones as covalent reversible inhibitors of the parasitic cysteine protease “rhodesain” have proven to be promising novel drug candidates.
Here, the team around Tanja focused on optimizing α-fluorovinylsulfones and -sulfonates for rhodesain inhibition using molecular modeling approaches. This resulted in highly potent and selective inhibitors with single-digit nanomolar affinity. The researchers further investigated the binding modes experimentally via MS experiments, indicating that the compounds are covalent-reversible, slow-tight binders. The different inhibition mechanisms of fluorinated and non-fluorinated compounds (reversible vs. irreversible) were investigated by QM/MM calculations and MD simulations.
In vivo studies revealed a favorable metabolism and biodistribution compared to non-optimized rhodesain inhibitors. Furthermore, they observed an anti-trypanosomal activity in the nanomolar range for inhibitors with an N-terminal 2,3-dihydrobenzo[b][1,4]dioxine group and a 4-Me-Phe residue in P2.

 

 

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