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Rhodesain is the main cysteine protease of <i>Trypanosoma brucei rhodesiense</i>, the parasite causing the acute lethal form of Human African Trypanosomiasis. Starting from the dipeptide nitrile <b>CD24</b>, the further introduction of a fluorine atom in the <i>meta</i> position of the phenyl ring spanning in the P3 site and the switch of the P2 leucine with a phenylalanine led to <b>CD34</b>, a synthetic inhibitor that shows a nanomolar binding affinity towards rhodesain (<i>K</i>_i = 27 nM) and an improved target selectivity with respect to the parent dipeptide nitrile <b>CD24</b>. In the present work, following the Chou and Talalay method, we carried out a combination study of <b>CD34</b> with curcumin, a nutraceutical obtained from <i>Curcuma longa L.</i> Starting from an affected fraction (f_a) of rhodesain inhibition of 0.5 (i.e., the IC₅₀), we observed an initial moderate synergistic action, which became a synergism for f_a values ranging from 0.6 to 0.7 (i.e., 60–70% inhibition of the trypanosomal protease). Interestingly, at 80–90% inhibition of rhodesain proteolytic activity, we observed a strong synergism, resulting in 100% enzyme inhibition. Overall, in addition to the improved target selectivity of <b>CD34</b> with respect to <b>CD24</b>, the combination of <b>CD34</b> + curcumin resulted in an increased synergistic action with respect to <b>CD24</b> + curcumin, thus suggesting that it is desirable to use <b>CD34</b> and curcumin in combination.