Advanced search
Start date

Molecular design and synthesis of reversible cruzain inhibitors

Grant number: 13/01128-0
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): May 01, 2013
Effective date (End): October 31, 2017
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Organic Chemistry
Principal Investigator:Carlos Alberto Montanari
Grantee:Daniel Gedder Silva
Host Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Associated scholarship(s):16/10362-5 - Synthesis of cruzain inhibitors for dipeptidyl nitriles warhead exchange, BE.EP.DR


The cruzain, a major Trypanosoma cruzi cysteine protease, is an enzyme essential for the life cycle of the parasite and has been used as a viable target for the search of enzyme inhibitors as drug candidates. The peptide-mimetic compound K11777 inhibits cruzain in nanomolar concentration and acts by a mechanism of irreversible inhibition. This strong interaction seems to be essential for the inhibition process and death of the parasite since several studies have shown that irreversible cruzain inhibition by small molecules, eradicate the infection caused by the parasite in cell cultures and animal models. Analogs or derivatives K11777 generally contain electrophilic functional groups known as "warheads" that can bind covalently to the active site via nucleophilic attack by the catalytic cysteine. Although this mechanism has been extensively studied, few other studies have explored the influence of the nature of the covalent bond in the process of reversible covalent inhibition in cruzain. This work will be carried out to a detailed computational study using 3D-QSAR (CoMFA / CoMSIA), covalent docking, molecular dynamics and free energy calculations of interaction for known inhibitors of cruzain to better understand the process of reversibility associated with inhibition and death of the parasite. Initially, a model will be developed with the goal of mapping the essential features for disclosing of any structure-activity relationships (SAR). The evaluation of this model will be carried out using data from both our laboratory as well as the current literature. Based on these results, new commercially putative cruzain inhibitors will be purchased and assayed to validate the model. Cysteine protease inhibitors are also susceptible to electrophilic nitriles to achieve potency at nanomolar concentrations. However, such inhibitors may have higher or lower off-target effects depending on the nature of the electrophilic substituted nitriles. Thus, in this project analogs and/or derivatives of bioactive compounds present in the models will be synthesized, when acceptable reactivity against thiol-nucleophiles is likely to be found. Compounds will be tested by fluorimetric methods, time-dependent, in order to experimentally quantify the contribution of the molecular changes in potency and selectivity against cruzain and cathepsin L. (AU)

News published in Agência FAPESP Newsletter about the scholarship:
Articles published in other media outlets (0 total):
More itemsLess items

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)
SILVA, DANIEL G.; RIBEIRO, JEAN F. R.; DE VITA, DANIELA; CIANNI, LORENZO; FRANCO, CAIO HADDAD; FREITAS-JUNIOR, LUCIO H.; MORAES, CAROLINA BORSOI; ROCHA, JOSMAR R.; BURTOLOSO, ANTONIO C. B.; KENNY, PETER W.; et al. A comparative study of warheads for design of cysteine protease inhibitors. Bioorganic & Medicinal Chemistry Letters, v. 27, n. 22, p. 5031-5035, . (13/18009-4, 13/01128-0, 16/10362-5, 15/14304-7)
SILVA, DANIEL GEDDER; ROCHA, JOSMAR RODRIGUES; SARTORI, GERALDO RODRIGUES; MONTANARI, CARLOS ALBERTO. Highly predictive hologram QSAR models of nitrile-containing cruzain inhibitors. JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, v. 35, n. 15, p. 3232-3249, . (13/18009-4, 13/01128-0, 16/10362-5)
SILVA, DANIEL G.; GILLESPIE, J. ROBERT; RANADE, RANAE M.; HERBST, ZACKARY M.; NGUYEN, UYEN T. T.; BUCKNER, FREDERICK S.; MONTANARI, CARLOS A.; GELB, MICHAEL H.. New Class of Antitrypanosomal Agents Based on Imidazopyridines. ACS Medicinal Chemistry Letters, v. 8, n. 7, p. 766-770, . (13/18009-4, 13/01128-0, 16/10362-5)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
SILVA, Daniel Gedder. Molecular design, synthesis and evaluation of cruzain inhibitors and antitrypanosomal agents based on imidazopyridines. 2017. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Química de São Carlos (IQSC/BT) São Carlos.

Please report errors in scientific publications list by writing to: