Drug combination studies of PS-1 and quercetin against rhodesain of <i>Trypanosoma brucei rhodesiense</i>

Chio, Carla Di; Previti, Santo; Luca, Fabiola De; Allegra, Alessandro; Zappalà, Maria; Ettari, Roberta

doi:10.1080/14786419.2021.1978993

Cited by 2 publications

(2 citation statements)

References 19 publications

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“…Following the rules of Chou and Talalay [34,35], we previously obtained an additive effect at the IC 50 for this combination. It became a slight-to-moderate synergism at 60-70% of the effect, and finally a synergism from 80% to 100% of rhodesain inhibition [30].…”

Section: Introductionmentioning

confidence: 97%

“…Recently, we developed a new class of dipeptide nitrile able to react with the catalytic cysteine of rhodesain by Pinner reaction, giving a reversible thiomidate adduct, thus identifying a novel lead compound, i.e., the dipeptide nitrile CD24, which showed a nanomolar binding affinity towards rhodesain (K i = 16 nM), coupled to a good antiparasitic activity (i.e., EC 50 = 10.1 ± 0.5 µM) [29]. Considering our know-how in drug combinations [30][31][32], we recently carried out a combination study on the lead compound CD24 with curcumin [33] (Figure 1), a potent multitarget nutraceutical extracted from Curcuma longa L., which we previously demonstrated to inhibit rhodesain in a non-competitive manner [31]. Following the rules of Chou and Talalay [34,35], we previously obtained an additive effect at the IC 50 for this combination.…”

Section: Introductionmentioning

confidence: 99%

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

Di Chio,

Previti,

Totaro

et al. 2023

IJMS

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Rhodesain is the main cysteine protease of Trypanosoma brucei rhodesiense, the parasite causing the acute lethal form of Human African Trypanosomiasis. Starting from the dipeptide nitrile CD24, the further introduction of a fluorine atom in the meta position of the phenyl ring spanning in the P3 site and the switch of the P2 leucine with a phenylalanine led to CD34, a synthetic inhibitor that shows a nanomolar binding affinity towards rhodesain (Ki = 27 nM) and an improved target selectivity with respect to the parent dipeptide nitrile CD24. In the present work, following the Chou and Talalay method, we carried out a combination study of CD34 with curcumin, a nutraceutical obtained from Curcuma longa L. Starting from an affected fraction (fa) of rhodesain inhibition of 0.5 (i.e., the IC50), we observed an initial moderate synergistic action, which became a synergism for fa 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 CD34 with respect to CD24, the combination of CD34 + curcumin resulted in an increased synergistic action with respect to CD24 + curcumin, thus suggesting that it is desirable to use CD34 and curcumin in combination.

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Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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

Di Chio,

Previti,

Totaro

et al. 2023

IJMS

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Drug Combination Studies of the Dipeptide Nitrile CD24 with Curcumin: A New Strategy to Synergistically Inhibit Rhodesain of Trypanosoma brucei rhodesiense

Chio

Previti

Luca

et al. 2022

IJMS

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Rhodesain is a cysteine protease that is crucial for the life cycle of Trypanosoma brucei rhodesiense, a parasite causing the lethal form of Human African Trypanosomiasis. CD24 is a recently developed synthetic inhibitor of rhodesain, characterized by a nanomolar affinity towards the trypanosomal protease (Ki = 16 nM), and acting as a competitive inhibitor. In the present work, we carried out a combination study of CD24 with curcumin, the multitarget nutraceutical obtained from Curcuma longa L., which we demonstrated to inhibit rhodesain in a non-competitive manner. By applying the Chou and Talalay method, we obtained an initial additive effect at IC50 (fa = 0.5, Combination Index = 1), while for the most relevant fa values, ranging from 0.6 to 1, i.e., from 60% to 100% of rhodesain inhibition, we obtained a combination index < 1, thus suggesting that an increasingly synergistic action occurred for the combination of the synthetic inhibitor CD24 and curcumin. Furthermore, the combination of the two inhibitors showed an antitrypanosomal activity better than that of CD24 alone (EC50 = 4.85 µM and 10.1 µM for the combination and CD24, respectively), thus suggesting the use of the two inhibitors in combination is desirable.

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Drug combination studies of PS-1 and quercetin against rhodesain of Trypanosoma brucei rhodesiense

Cited by 2 publications

References 19 publications

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

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

Drug Combination Studies of the Dipeptide Nitrile CD24 with Curcumin: A New Strategy to Synergistically Inhibit Rhodesain of Trypanosoma brucei rhodesiense

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