Abstract
Azapeptide nitriles are postulated to reversibly covalently react with the active-site cysteine residue of cysteine proteases and form isothiosemicarbazide adducts. We investigated the interaction of azadipeptide nitriles with the cathepsin B1 drug target (SmCB1) from Schistosoma mansoni, a pathogen that causes the global neglected disease schistosomiasis. Azadipeptide nitriles were superior inhibitors of SmCB1 over their parent carba analogs. We determined the crystal structure of SmCB1 in complex with an azadipeptide nitrile and analyzed the reaction mechanism using quantum chemical calculations. The data demonstrate that azadipeptide nitriles, in contrast to their carba counterparts, undergo a change from E- to Z-configuration upon binding, which gives rise to a highly favorable energy profile of noncovalent and covalent complex formation. Finally, azadipeptide nitriles were considerably more lethal than their carba analogs against the schistosome pathogen in culture, supporting the further development of this chemotype as a treatment for schistosomiasis.
Highlights
Azapeptide nitriles are postulated to reversibly covalently react with the active-site cysteine residue of cysteine proteases and form isothiosemicarbazide adducts
Compared to their parent carbapeptide analogs, bioactive azapeptides can possess improved potency and target selectivity as well as superior pharmacokinetics.[1−5] Azadipeptide nitriles were introduced as a class of efficient inhibitors of human cysteine cathepsins.[6−9] This chemotype supported the successful development of activity-based probes, modified for organelle-specific delivery to lysosomal cysteine proteases and applied as PET-imaging agents for tumor-associated cathepsin activity.[10−12] These reports have highlighted that azadipeptide nitriles can enrich the portfolio of inhibitors of cysteine proteases suitable as activity-based probes[13,14] and potential therapeutics against parasitic and protozoal infections.[15−18]
We have evaluated a set of 18 azadipeptide and 50 carbadipeptide nitriles in vitro as potential inhibitors of the SmCB1 protease
Summary
The linear dependence of the kobs values on the inhibitor concentrations (Figure 2) indicates a one-step kinetic reaction mechanism of the slow-binding azanitrile inhibitor,[43] which is, composed of several distinct mechanistic events in the physicochemical reaction scheme. On the basis of computational analysis, E- to Z-conversion is the kinetic controlling step, while the covalent bond formation is not supposed to be attributed to the slow binding because the transition barrier TS2 of azanitrile is even lower than that of the fast-binding carbanitrile. Except for compound 3c, the inhibitors used in this study have been synthesized as described.[6−8,47] Thin-layer chromatography was carried out on Merck (Darmstadt, Germany) aluminum sheets, silica gel 60 F254. Preparative column chromatography was performed on Merck silica gel (0.063−0.200 mm, 60 Å). Melting points were determined on a Büchi (Essen, Germany) 510 oil bath apparatus. 1H NMR (500 MHz) and 13C NMR (125 MHz) spectra were recorded on a Bruker Avance DRX 500 spectrometer and 1H NMR (600 MHz) and 13C NMR
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