On the intrinsic reactivity of highly potent trypanocidal cruzain inhibitors

Autor(es):Mostrar menos -

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: RSC MEDICINAL CHEMISTRY; v. 11, n. 11, p. 1275-1284, NOV 1 2020.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 18/21749-3 - Estudo computacional da reação de inibição da enzima cruzaína por inibidores covalentes reversíveis
• Beneficiário: Carlos Alberto Montanari
• Modalidade de apoio: Auxílio à Pesquisa - Pesquisador Visitante - Brasil
• Processo FAPESP: 18/15904-6 - Caracterização de inibidores de cisteíno proteases com atividade antineoplásica por meio de ensaios in silico, celulares e análise química
• Beneficiário: Andrei Leitão
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/18009-4 - Planejamento, síntese e atividade tripanossomicida de inibidores covalentes reversíveis da enzima cruzaína
• Beneficiário: Carlos Alberto Montanari
• Modalidade de apoio: Auxílio à Pesquisa - Temático