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Molecular design and synthesis of new cruzain inhibitors with trypanocidal activity

Grant number: 17/17386-0
Support type:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): January 01, 2018
Effective date (End): December 31, 2018
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Organic Chemistry
Principal researcher:Carlos Alberto Montanari
Grantee:Lorenzo Cianni
Supervisor abroad: Jurgen Bajorath
Home Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Research place: Eberhard Karls Universität Tübingen, Germany  
Associated to the scholarship:16/07946-5 - Synthesis and evaluation of trypanocidal activity of potential reversible covalent inhibitors of cruzain enzyme, BP.DD


Cruzain is an established target for the identification of novel trypanocidal agents, but how good are in vitro/in vivo correlations for active compounds? This project aims at the development of computational models for the prediction of the properties of cruzain inhibitors that are Trypanosoma cruzi killers. We will systematically analyze structure-activity relationships (SARs), visualize SARs, explore molecular similarity, and predict novel active compounds. Data sets will comprise ChEMBL cruzain inhibitors and a selection of trypanocidal agents that act by killing the T. cruzi infective forms Tulahuen, CL-Brener and Y. We will calibrate a number of cruzain inhibitors with T. cruzi killers in order to identify common properties that characterize drug-likeness represented in many established cruzain inhibitors. We will then try to correlate this with the evidence that many high affinity cruzain inhibitors are not trypanocidal agents against T. cruzi. Computational modeling will lead to the synthesis of new trypanocidal agents designed on the basis of this work - that is, compounds with an imprinted action on cruzain that can kill T. cruzi. We will also try to achieve selectivity of these inhibitors over other cysteine proteases like cathepsin L. (AU)

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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)
CIANNI, LORENZO; LEMKE, CARINA; GILBERG, ERIK; FELDMANN, CHRISTIAN; ROSINI, FABIANA; ROCHO, FERNANDA DOS REIS; RIBEIRO, JEAN F. R.; TEZUKA, DAIANE Y.; LOPES, CARLA D.; DE ALBUQUERQUE, SERGIO; BAJORATH, JUERGEN; LAUFER, STEFAN; LEITAO, ANDREI; GUETSCHOW, MICHAEL; MONTANARI, CARLOS A. Mapping the S1 and S1' subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents. PLoS Neglected Tropical Diseases, v. 14, n. 3 MAR 2020. Web of Science Citations: 5.

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