title: Gold compounds as cysteine protease inhibitors: perspectives for pharmaceutical application as antiparasitic agents.
abstract: Gold compounds form a new class of promising metal-based drugs with a number of potential therapeutic applications, particularly in the fields of anticancer and antimicrobial treatments. Previous research revealed that a group of structurally diverse gold compounds cause conspicuous inhibition of the protease activities of the human proteasome. Given the pharmacological importance of protease inhibition, the present study further explored whether these gold compounds might inhibit a few other proteases that are accepted druggable targets for disease treatment. In particular, four distinct cysteine proteases were considered here: cathepsin B and L that play a primary role in tumor-cell invasion and metastasis; rhodesain, the major cathepsin L-like cysteine protease of Trypanosoma brucei rhodesiense and CPB2.8ΔCTE, a Leishmania mexicana mature cysteine protease. Based on the encouraging results obtained for some of the tested gold compounds on the two parasitic cysteine proteases, especially against CPB2.8ΔCTE, with IC50sin the micromolar range, we next evaluated whether those gold compounds might contrast effectively the growth of the respective protozoa and indeed important antiprotozoal properties were disclosed; on the other hand a certain lack of selectivity was highlighted. Also, no direct or clear correlation could be established between the in vitro antiprotozoal properties and the level of protease inhibition. The implications of these results are discussed in relation to possible pharmaceutical applications.
authors.affiliation: (MetMed) Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019, Sesto Fiorentino, Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Massai
authors.affiliation: (MetMed) Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019, Sesto Fiorentino, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Messori
authors.affiliation: Laboratory of Nanomedicine, Biomaterials and Heterocyclic Compounds, Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, via F. Stagno D'Alcontres 31, 98166, Messina, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Micale
authors.affiliation: Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55099, Mainz, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
authors.affiliation: Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.affiliation: Department of Chemical Sciences, University of Padova, Via Marzolo 1, 35131, Padua, Italy.
authors.forename: Dolores
authors.initials: D
authors.lastname: Fregona
authors.affiliation: Department of Chemistry and Pharmacy, University of Sassari, Via Vienna 2, 07100, Sassari, Italy.
authors.forename: Maria Agostina
authors.initials: MA
authors.lastname: Cinellu
authors.affiliation: Department of Chemistry and Industrial Chemistry, University of Pisa, via Moruzzi, 13, 56124, Pisa, Italy. chiara.gabbiani@unipi.it.
authors.forename: Chiara
authors.identifier: 0000-0002-8468-4838
authors.initials: C
authors.lastname: Gabbiani
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000737:chemistry; D056668:Cathepsin L / Q000037:antagonists & inhibitors / Q000737:chemistry; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D018314:Leishmania infantum / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D050607:Organogold Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development
chemical_list: D000981:Antiprotozoal Agents; D015853:Cysteine Proteinase Inhibitors; D050607:Organogold Compounds; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D003546:Cysteine Endopeptidases; C446033:rhodesain; C533912:CTSB protein, human; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; D046988:Proteasome Endopeptidase Complex
keywords: Cysteine proteases; Enzyme inhibition; Gold compounds; Parasitic protozoa