title: Anti-trypanosomal activity of non-peptidic nitrile-based cysteine protease inhibitors.
abstract: The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. Anti-trypanosomal activity against the CL Brener strain of T. cruzi was observed in the 0.1 μM to 1 μM range for three nitrile-based cysteine protease inhibitors based on two scaffolds known to be associated with cathepsin K inhibition. The two compounds showing the greatest potency against the trypanosome were characterized by EC50 values (0.12 μM and 0.25 μM) that were an order of magnitude lower than the corresponding Ki values measured against cruzain, a recombinant form of cruzipain, in an enzyme inhibition assay. This implies that the anti-trypanosomal activity of these two compounds may not be explained only by the inhibition of the cruzain enzyme, thereby triggering a putative polypharmacological profile towards cysteine proteases.
authors.affiliation: Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brasil.
authors.forename: Antonio C B
authors.initials: AC
authors.lastname: Burtoloso
authors.affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Sérgio
authors.initials: S
authors.lastname: de Albuquerque
authors.affiliation: AstraZeneca, Mölndal, Sweden.
authors.forename: Mark
authors.initials: M
authors.lastname: Furber
authors.affiliation: Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brasil.
authors.forename: Juliana C
authors.initials: JC
authors.lastname: Gomes
authors.affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Gonçalez
authors.affiliation: Grupo de Estudos em Química Medicinal - NEQUIMED, Instituto de Química de São Carlos - Universidade de São Paulo, São Carlos, São Paulo, Brazil.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Kenny
authors.affiliation: Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brasil.|Grupo de Estudos em Química Medicinal - NEQUIMED, Instituto de Química de São Carlos - Universidade de São Paulo, São Carlos, São Paulo, Brazil.
authors.forename: Andrei
authors.initials: A
authors.lastname: Leitão
authors.affiliation: Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brasil.|Grupo de Estudos em Química Medicinal - NEQUIMED, Instituto de Química de São Carlos - Universidade de São Paulo, São Carlos, São Paulo, Brazil.
authors.forename: Carlos A
authors.identifier: 0000-0002-4963-0316
authors.initials: CA
authors.lastname: Montanari
authors.affiliation: Grupo de Estudos em Química Medicinal - NEQUIMED, Instituto de Química de São Carlos - Universidade de São Paulo, São Carlos, São Paulo, Brazil.
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Quilles
authors.affiliation: Grupo de Estudos em Química Medicinal - NEQUIMED, Instituto de Química de São Carlos - Universidade de São Paulo, São Carlos, São Paulo, Brazil.
authors.forename: Jean F R
authors.initials: JF
authors.lastname: Ribeiro
authors.affiliation: Grupo de Estudos em Química Medicinal - NEQUIMED, Instituto de Química de São Carlos - Universidade de São Paulo, São Carlos, São Paulo, Brazil.
authors.forename: Josmar R
authors.initials: JR
authors.lastname: Rocha
mesh_terms: D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D015853:Cysteine Proteinase Inhibitors; D009570:Nitriles; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi