Molecular design, synthesis, and trypanocidal activity of reversible covalent inhibitors of cruzain enzyme

• Grant number: 18/03985-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: June 01, 2018
• End date: April 30, 2020
• Field of knowledge: Physical Sciences and Mathematics - Chemistry
• Principal Investigator: Carlos Alberto Montanari
• Grantee: Anwar Shamim
• 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

Cysteine proteases provide targets useful for the treatment of various diseases that affect humans. In disorders caused by parasitic infection, cruzain is a target for enzymatic inhibition. The reactive and active catalytic cysteine site (Cys25) provides specificity for many inhibitors, but obtaining selectivity within families of cysteine proteases and their isoenzymes can be problematic. The reason for this, however, is not in the eventual ability to identify promiscuous inhibitors, but in the possibility of searching for enzymatic inhibitors with application in other disease state models, as we have done extensively in NEQUIMED/IQSC/USP. The results obtained so far, indicate the existence of selective cruzain inhibitors in 2-3 log units in relation to its counter-target cathepsin L. (AU)

Scientific publications

(5)

(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; ROCHO, FERNANDA DOS REIS; BONATTO, VINICIUS; PRADO MARTINS, FELIPE CARDOSO; LAMEIRA, JERONIMO; LEITAO, ANDREI; MONTANARI, CARLOS A.; SHAMIM, ANWAR. Design, synthesis and stepwise optimization of nitrile-based inhibitors of cathepsins B and L. Bioorganic & Medicinal Chemistry, v. 29, JAN 1 2021. (13/18009-4, 18/03985-1, 16/07946-5)

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)

CIANNI, LORENZO; ROCHO, FERNANDA DOS REIS; ROSINI, FABIANA; BONATTO, VINICIUS; RIBEIRO, JEAN F. R.; LAMEIRA, JERONIMO; LEITAO, ANDREI; SHAMIM, ANWAR; MONTANARI, CARLOS A.. Optimization strategy of single-digit nanomolar cross-class inhibitors of mammalian and protozoa cysteine proteases. BIOORGANIC CHEMISTRY, v. 101, AUG 2020. (13/18009-4, 16/07946-5, 18/03985-1)

QUILLES, JR., JOSE C.; SHAMIM, ANWAR; TEZUKA, DAIANE Y.; BATISTA, PEDRO H. J.; LOPES, CARLA D.; DE ALBUQUERQUE, SERGIO; MONTANARI, CARLOS A.; LEITAO, ANDREI. Dipeptidyl nitrile derivatives suppress the Trypanosoma cruzi in vitro infection. Experimental Parasitology, v. 219, DEC 2020. (13/18009-4, 18/15904-6, 18/03985-1, 14/07292-0)

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)