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 (ECY.strain50 = 0.1 μM; SI = 58.4) than the current drug benznidazole (ECY.strain50 = 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.

On the intrinsic reactivity of highly potent trypanocidal cruzain inhibitors / Bonatto, V.; Batista, P. H. J.; Cianni, L.; De Vita, D.; Silva, D. G.; Cedron, R.; Tezuka, D. Y.; De Albuquerque, S.; Moraes, C. B.; Franco, C. H.; Lameira, J.; Leitao, A.; Montanari, C. A.. - In: RSC MEDICINAL CHEMISTRY. - ISSN 2632-8682. - 11:11(2020), pp. 1275-1284. [10.1039/d0md00097c]

On the intrinsic reactivity of highly potent trypanocidal cruzain inhibitors

De Vita D.;
2020

Abstract

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 (ECY.strain50 = 0.1 μM; SI = 58.4) than the current drug benznidazole (ECY.strain50 = 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.
2020
cysteine proteases; Chagas disease; peptidomimetic inhibitors
01 Pubblicazione su rivista::01a Articolo in rivista
On the intrinsic reactivity of highly potent trypanocidal cruzain inhibitors / Bonatto, V.; Batista, P. H. J.; Cianni, L.; De Vita, D.; Silva, D. G.; Cedron, R.; Tezuka, D. Y.; De Albuquerque, S.; Moraes, C. B.; Franco, C. H.; Lameira, J.; Leitao, A.; Montanari, C. A.. - In: RSC MEDICINAL CHEMISTRY. - ISSN 2632-8682. - 11:11(2020), pp. 1275-1284. [10.1039/d0md00097c]
File allegati a questo prodotto
File Dimensione Formato  
Bonatto_On-the-intrinsic_2020.pdf

solo gestori archivio

Tipologia: Documento in Post-print (versione successiva alla peer review e accettata per la pubblicazione)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 2.01 MB
Formato Adobe PDF
2.01 MB Adobe PDF   Contatta l'autore

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1482023
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 7
  • ???jsp.display-item.citation.isi??? 7
social impact