On the intrinsic reactivity of highly potent trypanocidal cruzain inhibitors
| Autor: | Carlos A. Montanari, Sérgio de Albuquerque, Daiane Y. Tezuka, Daniel G. Silva, Caio Haddad Franco, Daniela De Vita, Andrei Leitão, Carolina B. Moraes, Jerônimo Lameira, Pedro Henrique Jatai Batista, Rodrigo Cedron, Vinícius Bonatto, Lorenzo Cianni |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Peptidomimetic
Stereochemistry Pharmaceutical Science Cruzipain 01 natural sciences Biochemistry cysteine proteases Chagas disease peptidomimetic inhibitors 03 medical and health sciences chemistry.chemical_compound Drug Discovery medicine Reactivity (chemistry) 030304 developmental biology Trypanocidal agent Pharmacology 0303 health sciences 010405 organic chemistry Chemistry Organic Chemistry Glutathione Cysteine protease 0104 chemical sciences Benznidazole Molecular Medicine medicine.drug Cysteine |
| Zdroj: | RSC Med Chem |
| ISSN: | 2632-8682 |
| Popis: | The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. Hence, peptidomimetic cruzipain inhibitors having a reactive group (known as warhead) are subject to continuous studies to discover novel antichagasic compounds. Here, we evaluated how different warheads for a set of structurally similar related compounds could inhibit the activity of cruzipain and, ultimately, their trypanocidal effect. We first investigated in silico the intrinsic reactivity of these compounds by applying the Fukui index to correlate it with the enzymatic affinity. Then, we evaluated their potency against T. cruzi (Y and Tulahuen strains), which revealed the reversible cruzain inhibitor Neq0656 as a better trypanocidal agent (EC(Y.strain)(50) = 0.1 μM; SI = 58.4) than the current drug benznidazole (EC(Y.strain)(50) = 5.1 μM; SI > 19.6). We also measured the half-life time by HPLC analysis of three lead compounds in the presence of glutathione and cysteine to experimentally assess their intrinsic reactivity. Results clearly illustrated the reactivity trend for the warheads (azanitrile > aldehyde > nitrile), where the aldehyde displayed an intermediate intrinsic reactivity. Therefore, the aldehyde bearing peptidomimetic compounds should be subject for in-depth evaluation in the drug discovery process. |
| Databáze: | OpenAIRE |
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