Inhibitor-Induced Dimerization of an Essential Oxidoreductase from African Trypanosomes

Trypanosomal and leishmanial infections claim tens of thousands of lives each year. The 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 parasite's hydroperoxide-clearance cascade. In vitro and in vivo functional assays show that a small, selective inhibitor efficiently inhibits Tpx. With X-ray crystallography, SAXS, analytical SEC, SEC-MALS, MD simulations, ITC, and NMR spectroscopy, we show how covalent binding of this monofunctional inhibitor leads to Tpx dimerization. Intra- and intermolecular inhibitor-inhibitor, pro…

Predicting 19F NMR Chemical Shifts: A Combined Computational and Experimental Study of a Trypanosomal Oxidoreductase–Inhibitor Complex

Abstract The absence of fluorine from most biomolecules renders it an excellent probe for NMR spectroscopy to monitor inhibitor–protein interactions. However, predicting the binding mode of a fluorinated ligand from a chemical shift (or vice versa) has been challenging due to the high electron density of the fluorine atom. Nonetheless, reliable 19F chemical‐shift predictions to deduce ligand‐binding modes hold great potential for in silico drug design. Herein, we present a systematic QM/MM study to predict the 19F NMR chemical shifts of a covalently bound fluorinated inhibitor to the essential oxidoreductase tryparedoxin (Tpx) from African trypanosomes, the causative agent of African sleepi…

Inhibitor-induzierte Dimerisierung einer essentiellen Oxidoreduktase aus afrikanischen Trypanosomen

Fluorovinylsulfones and -Sulfonates as Potent Covalent Reversible Inhibitors of the Trypanosomal Cysteine Protease Rhodesain: Structure–Activity Relationship, Inhibition Mechanism, Metabolism, and In Vivo Studies

Rhodesain is a major cysteine protease of Trypanosoma brucei rhodesiense, a pathogen causing Human African Trypanosomiasis, and a validated drug target. Recently, we reported the development of α-halovinylsulfones as a new class of covalent reversible cysteine protease inhibitors. Here, α-fluorovinylsulfones/-sulfonates were optimized for rhodesain based on molecular modeling approaches. 2d, the most potent and selective inhibitor in the series, shows a single-digit nanomolar affinity and high selectivity toward mammalian cathepsins B and L. Enzymatic dilution assays and MS experiments indicate that 2d is a slow-tight binder (Ki = 3 nM). Furthermore, the nonfluorinated 2d-(H) shows favorabl…

Donor–Acceptor Polymers for Electrochemical Supercapacitors: Synthesis, Testing, and Theory

Donor–acceptor polymers can store both a positive and negative charge allowing them to function as both the positive and negative charge storage material in a supercapacitor device, however few have been explored for this application. Here, we describe the synthesis of several donor–acceptor polymers and their electrodeposited polymer electrodes. We use differing molecular structures to examine the effect of electron acceptor concentration and show that device stability can be improved significantly by increasing the acceptor concentration. Further, we provide computational insight into the important chemical requirements for achieving even higher performance supercapacitors based on donor–…

CCDC 1981158: Experimental Crystal Structure Determination

Related Article: Philipp Klein, Patrick Johè, Fabian Barthels, Annika Wagner, Stefan Tenzer, Ute Distler, Thien Anh Le, Bernd Engels, Ute A. Hellmich, Till Opatz, Tanja Schirmeister|2020|Molecules|25|2064|doi:10.3390/molecules25092064

CCDC 1862408: Experimental Crystal Structure Determination

Related Article: Annika Wagner, Thien Anh Le, Martha Brennich, Philipp Klein, Nicole Bader, Erika Diehl, Daniel Paszek, A. Katharina Weickhmann, Natalie Dirdjaja, R. Luise Krauth-Siegel, Bernd Engels, Till Opatz, Hermann Schindelin, Ute A. Hellmich|2019|Angew.Chem.,Int.Ed.|58|3640|doi:10.1002/anie.201810470