On the intrinsic reactivity of highly potent trypanocidal cruzain inhibitors

Author(s):Show less -

Bonatto, Vinicius ^[1] ; Jatai Batista, Pedro Henrique ^[1] ; Cianni, Lorenzo ^[1] ; De Vita, Daniela ^[1] ; Silva, Daniel G. ^[1] ; Cedron, Rodrigo ^[1] ; Tezuka, Daiane Y. ^{[1, 2]} ; de Albuquerque, Sergio ^[2] ; Moraes, Carolina Borsoi ^[3] ; Franco, Caio Haddad ^[3] ; Lameira, Jeronimo ^{[1, 4]} ; Leitao, Andrei ^[1] ; Montanari, Carlos A. ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Chem Sao Carlos, Med Chem Grp, Ave Trabalhador Sancarlense 400, BR-23566590 Sao Carlos, SP - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Sch Pharmaceut Sci, Ribeirao Preto, SP - Brazil

^[3] Ctr Nacl Pesquisa Energia & Mat CNPEM, Lab Nacl Biociencias LNBio, Campinas, SP - Brazil

^[4] Univ Fed Para, Inst Ciencias Exatas & Nat, Lab Planejamento & Desenvolvimento Farmacos, Rua Augusto Correa 01, BR-66075110 Belem, Para - Brazil

• Document type: Journal article
• Source: RSC MEDICINAL CHEMISTRY; v. 11, n. 11, p. 1275-1284, NOV 1 2020.
• Web of Science Citations: 0

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 (ECY50Y.strain = 0.1 mu M; SI = 58.4) than the current drug benznidazole (EC50Y.strain = 5.1 mu M; 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. (AU)

• FAPESP's process: 18/21749-3 - Computational study of cruzain enzyme by reversible covalent inhibitors
• Grantee: Carlos Alberto Montanari
• Support Opportunities: Research Grants - Visiting Researcher Grant - Brazil
• FAPESP's process: 18/15904-6 - Characterization of cysteine protease inhibitors with antineoplastic activity by in silico and cell-based assays coupled with chemical analyses
• Grantee: Andrei Leitão
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors
• Grantee: Carlos Alberto Montanari
• Support Opportunities: Research Projects - Thematic Grants