Dipeptide Nitrile CD34 with Curcumin: A New Improved Combination Strategy to Synergistically Inhibit Rhodesain of .

Rhodesain is the main cysteine protease of , the parasite causing the acute lethal form of Human African Trypanosomiasis. Starting from the dipeptide nitrile , the further introduction of a fluorine atom in the position of the phenyl ring spanning in the P3 site and the switch of the P2 leucine with a phenylalanine led to , a synthetic inhibitor that shows a nanomolar binding affinity towards rhodesain ( = 27 nM) and an improved target selectivity with respect to the parent dipeptide nitrile . In the present work, following the Chou and Talalay method, we carried out a combination study of with curcumin, a nutraceutical obtained from Starting from an affected fraction (f) of rhodesain inhibition of 0.5 (i.e., the IC), we observed an initial moderate synergistic action, which became a synergism for f 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 with respect to , the combination of + curcumin resulted in an increased synergistic action with respect to + curcumin, thus suggesting that it is desirable to use and curcumin in combination.