Anti-Trypanosoma cruzi activity of non-Peptidic agents as inhibitors of cysteine protease cruzain

• Grant number: 18/03279-0
• Support Opportunities: Scholarships in Brazil - Master
• Start date: May 01, 2018
• End date: February 29, 2020
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Carlos Alberto Montanari
• Grantee: Rafael da Fonseca Lameiro
• Host Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Associated research grant: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors, AP.TEM

Abstract

Trypanosoma cruzi is a flagellated parasite that causes Chagas disease. This parasite depends on cruzipain, a cysteine protease essential for its survival. Our research group has identified inhibitors of recombinant cruzain which are tripanosomicide drug candidates for the treatment of Chagas disease. These are dipeptidyl nitriles that inhibit cysteine proteases of the papain family and therefore find pharmacological applications in different states of diseases. They are reversible covalent inhibitors in which the reactivity of the nitrile group makes them excellent molecular skeletons for structural modification. Recently, we have identified the cruzain inhibitor Neq0594 (pKi = 5.6) which is more potent as an anti-T. cruzi agent (pEC50 = 6.9) than the control drug - benznidazole (pEC50 = 5.8). It is a bioisosteric tripanosomicide agent of dipeptidyl nitriles in the position P3 in which the trifluoroamino group in the configuration ((2S)-N-(1-cyanocyclopropyl)-3-phenyl-2-{[(1R) -2,2,2-trifluoro-1-phenylethyl]amino} propanamide) is more potent than its isomer (S), Neq0631 (pEC50 = 5.0). Nevertheless, cruzain has a greater affinity for Neq0631 (pKi = 5.9). As the anti-T. cruzi activity of Neq0594 is greater than the expected (pEC50Neq0594-pEC50Neq0631 = 1.9), in this project we will investigate the molecular reasons of this activity cliff. In other words, why is the tripanosomicide agent Neq0594 the eutomer, that is, the most pharmacologically potent enantiomer? (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

LAMEIRO, RAFAEL DA FONSECA; SHAMIM, ANWAR; ROSINI, FABIANA; CENDRON, RODRIGO; JATAI BATISTA, PEDRO HENRIQUE; MONTANARI, CARLOS ALBERTO. Synthesis, biochemical evaluation and molecular modeling studies of nonpeptidic nitrile-based fluorinated compounds. Future Medicinal Chemistry, v. 13, n. 1, p. 25-44, JAN 2021. (18/03279-0, 18/03985-1, 13/18009-4)

LAMEIRO, RAFAEL DA FONSECA; SHAMIM, ANWAR; ROSINI, FABIANA; CENDRON, RODRIGO; JATAI BATISTA, PEDRO HENRIQUE; MONTANARI, CARLOS ALBERTO. Synthesis, biochemical evaluation and molecular modeling studies of nonpeptidic nitrile-based fluorinated compounds. Future Medicinal Chemistry, DEC 2020. (18/03279-0, 18/03985-1, 13/18009-4)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

LAMEIRO, Rafael da Fonseca. Anti-Trypanosoma cruzi activity of non-peptidic agentes as inhibitors of the cysteine protease cruzain. 2020. Master's Dissertation - Universidade de São Paulo (USP). Instituto de Química de São Carlos (IQSC/BT) São Carlos.