title: Calpains: potential targets for alternative chemotherapeutic intervention against human pathogenic trypanosomatids.
abstract: The treatment for both leishmaniasis and trypanosomiasis, which are severe human infections caused by trypanosomatids belonging to Leishmania and Trypanosoma genera, respectively, is extremely limited because of concerns of toxicity and efficacy with the available anti-protozoan drugs, as well as the emergence of drug resistance. Consequently, the urgency for the discovery of new trypanosomatid targets and novel bioactive compounds is particularly necessary. In this context, the investigation of changes in parasite gene expression between drug resistant/sensitive strains and in the up-regulation of virulence-related genes in infective forms has brought to the fore the involvement of calpain-like proteins in several crucial pathophysiological processes performed by trypanosomatids. These studies were encouraged by the publication of the complete genome sequences of three human pathogenic trypanosomatids, Trypanosoma brucei, Trypanosoma cruzi and Leishmania major, which allowed in silico analyses that in turn directed the identification of numerous genes with interesting chemotherapeutic characteristics, including a large family of calpain-related proteins, in which to date 23 genes were assigned as calpains in T. brucei, 40 in T. cruzi and 33 in L. braziliensis. In the present review, we intend to add to these biochemical/biological reports the investigations performed upon the inhibitory capability of calpain inhibitors against human pathogenic trypanosomatids.
authors.affiliation: Laboratório de Investigação de Peptidases, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes-IMPG, Centro de Ciências da Saúde-CCS, Bloco Esubsolo, Sala 05, Universidade Federal do Rio de Janeiro-UFRJ, Rio de Janeiro, Brazil. mbranquinha@micro.ufrj.br
authors.forename: M H
authors.initials: MH
authors.lastname: Branquinha
authors.forename: F A
authors.initials: FA
authors.lastname: Marinho
authors.forename: L S
authors.initials: LS
authors.lastname: Sangenito
authors.forename: S S C
authors.initials: SS
authors.lastname: Oliveira
authors.forename: K C
authors.initials: KC
authors.lastname: Goncalves
authors.forename: V
authors.initials: V
authors.lastname: Ennes-Vidal
authors.forename: C M
authors.initials: CM
authors.lastname: d'Avila-Levy
authors.forename: A L S
authors.initials: AL
authors.lastname: Santos
mesh_terms: D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014345:Trypanosoma / Q000187:drug effects / Q000201:enzymology; D014352:Trypanosomiasis / Q000188:drug therapy* / Q000469:parasitology
chemical_list: D010455:Peptides; D011480:Protease Inhibitors; D015800:Protozoan Proteins; D002154:Calpain
references.citation: Biochem J. 1997 Dec 15;328 ( Pt 3):721-32
references.pmid: 9396712
references.citation: Trends Mol Med. 2001 Aug;7(8):355-62
references.pmid: 11516996
references.citation: J Mol Neurosci. 2003;20(3):357-62
references.pmid: 14501020
references.citation: Drug Discov Today. 2006 Oct;11(19-20):917-23
references.pmid: 16997142
references.citation: Biol Chem. 2002 May;383(5):739-49
references.pmid: 12108538
references.citation: J Med Chem. 2009 Dec 10;52(23):7339-59
references.pmid: 19606868
references.citation: J Antimicrob Chemother. 2010 Jul;65(7):1395-8
references.pmid: 20457672
references.citation: Mol Cell Biol. 2007 Apr;27(7):2548-61
references.pmid: 17210638
references.citation: Mol Cell Biochem. 1993 Sep 8;126(1):9-16
references.pmid: 8107694
references.citation: Genome Biol. 2007;8(6):218
references.pmid: 17608959
references.citation: Mol Cell Biochem. 2006 Jan;281(1-2):27-33
references.pmid: 16328954
references.citation: Trends Biochem Sci. 1991 Apr;16(4):150-3
references.pmid: 1877091
references.citation: PLoS One. 2011;6(11):e27634
references.pmid: 22096606
references.citation: Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14376-81
references.pmid: 11121041
references.citation: Proteomics. 2009 Apr;9(7):1782-94
references.pmid: 19288526
references.citation: J Mol Evol. 2005 Dec;61(6):742-57
references.pmid: 16315106
references.citation: Annu Rev Microbiol. 1993;47:821-53
references.pmid: 8257117
references.citation: Mol Biochem Parasitol. 2000 Jun;109(1):47-59
references.pmid: 10924756
references.citation: Biochem Biophys Res Commun. 1998 Apr 17;245(2):289-94
references.pmid: 9571143
references.citation: Physiol Rev. 2003 Jul;83(3):731-801
references.pmid: 12843408
references.citation: Exp Parasitol. 1999 Jul;92(3):183-91
references.pmid: 10403759
references.citation: Mol Biochem Parasitol. 2003 Jun;129(1):103-14
references.pmid: 12798511
references.citation: Trends Pharmacol Sci. 1994 Nov;15(11):412-9
references.pmid: 7855906
references.citation: Mol Biochem Parasitol. 1996 Dec 20;83(2):141-52
references.pmid: 9027747
references.citation: Ann N Y Acad Sci. 1999 Nov 28;884:52-9
references.pmid: 10842583
references.citation: Infect Immun. 2010 Jan;78(1):22-31
references.pmid: 19858295
references.citation: Annu Rev Biochem. 2002;71:275-305
references.pmid: 12045098
references.citation: Mem Inst Oswaldo Cruz. 2008 Sep;103(6):598-601
references.pmid: 18949332
references.citation: Int J Biochem Cell Biol. 2009 Oct;41(10):2069-80
references.pmid: 19379828
references.citation: Mol Biochem Parasitol. 2010 Jan;169(1):20-6
references.pmid: 19766148
references.citation: PLoS One. 2011 Apr 04;6(4):e18371
references.pmid: 21483751
references.citation: Expert Rev Mol Med. 2009 Oct 29;11:e31
references.pmid: 19863838
references.citation: Parasitol Res. 2012 Jun;110(6):2533-40
references.pmid: 22205353
references.citation: Infect Immun. 2002 Jul;70(7):3727-35
references.pmid: 12065515
references.citation: Cell Death Differ. 2002 Jan;9(1):65-81
references.pmid: 11803375
references.citation: Mem Inst Oswaldo Cruz. 2009 Jul;104 Suppl 1:263-9
references.pmid: 19753483
references.citation: J Proteome Res. 2008 Jun;7(6):2357-67
references.pmid: 18435557
references.citation: Curr Pharm Des. 2002;8(4):269-85
references.pmid: 11860366
references.citation: Biochem Biophys Res Commun. 2004 Mar 12;315(3):710-8
references.pmid: 14975759
references.citation: Int J Parasitol. 2000 Apr 10;30(4):329-45
references.pmid: 10731558
references.citation: Parasitology. 2009 Apr;136(4):433-41
references.pmid: 19250597
references.citation: J Biochem. 1989 Aug;106(2):274-81
references.pmid: 2553682
references.citation: Protist. 2009 Nov;160(4):576-90
references.pmid: 19656721
references.citation: Arch Biochem Biophys. 2003 Dec 1;420(1):1-8
references.pmid: 14622969
references.citation: Mem Inst Oswaldo Cruz. 1998 Nov-Dec;93(6):753-60
references.pmid: 9921298
references.citation: Parasitology. 2009 Jan;136(1):45-54
references.pmid: 19126269
references.citation: Trends Plant Sci. 2003 Feb;8(2):58-62
references.pmid: 12597871
references.citation: Adv Exp Med Biol. 2011;712:100-15
references.pmid: 21660661
references.citation: Parasitology. 2006;132 Suppl:S19-32
references.pmid: 17018162
references.citation: Mol Biochem Parasitol. 2001 Aug;116(1):25-34
references.pmid: 11463463
references.citation: FEMS Microbiol Lett. 2004 Sep 1;238(1):213-9
references.pmid: 15336424
references.citation: Drug News Perspect. 1998 May;11(4):215-22
references.pmid: 15616663
references.citation: EMBO J. 1999 Dec 15;18(24):6880-9
references.pmid: 10601010
references.citation: Neurosci Res. 1997 Jan;27(1):93-7
references.pmid: 9089703
references.citation: J Neurochem. 2005 Jun;93(5):1280-92
references.pmid: 15934947
references.citation: Brain Res. 1997 Jul 25;763(2):145-58
references.pmid: 9296555
references.citation: Mem Inst Oswaldo Cruz. 1999;94 Suppl 1:139-41
references.pmid: 10677701
references.citation: Acta Trop. 1981 Mar;38(1):29-37
references.pmid: 6111914
references.citation: Mol Cell Proteomics. 2007 Jan;6(1):88-101
references.pmid: 17050524
references.citation: J Cell Sci. 2005 Jan 15;118(Pt 2):283-90
references.pmid: 15654017
references.citation: Microbes Infect. 2006 Mar;8(3):637-44
references.pmid: 16469521
references.citation: Genomics. 1997 Oct 1;45(1):175-84
references.pmid: 9339374
references.citation: J Biol Chem. 1994 Oct 7;269(40):25137-42
references.pmid: 7929201
references.citation: Expert Opin Ther Pat. 2011 May;21(5):601-36
references.pmid: 21434837
references.citation: Mol Biol Cell. 2004 Nov;15(11):4775-86
references.pmid: 15342784
references.citation: Curr Protein Pept Sci. 2001 Jun;2(2):137-53
references.pmid: 12370021
references.citation: FEMS Microbiol Lett. 2006 Jan;254(1):149-56
references.pmid: 16451193
references.citation: Curr Pharm Des. 2001 Aug;7(12):1143-56
references.pmid: 11472258
references.citation: J Proteome Res. 2009 Jul;8(7):3642-52
references.pmid: 19374451
references.citation: Adv Parasitol. 1999;44:1-39
references.pmid: 10563394
references.citation: Int J Antimicrob Agents. 2006 Aug;28(2):138-42
references.pmid: 16842979
references.citation: Curr Opin Infect Dis. 2008 Dec;21(6):668-72
references.pmid: 18978536
references.citation: Int J Parasitol. 1994 Dec;24(8):1317-31
references.pmid: 7729984
references.citation: Trends Parasitol. 2003 Nov;19(11):488-94
references.pmid: 14580959
references.citation: An Acad Bras Cienc. 2006 Dec;78(4):687-714
references.pmid: 17143406
references.citation: Curr Top Med Chem. 2002 Nov;2(11):1261-71
references.pmid: 12171584
references.citation: Acta Trop. 2010 Jul-Aug;115(1-2):55-68
references.pmid: 19900395
references.citation: Antimicrob Agents Chemother. 2004 Mar;48(3):852-9
references.pmid: 14982775