A cysteine protease inhibitor cures Chagas' disease in an immunodeficient-mouse model of infection.
Chagas' disease, caused by the parasite Trypanosoma cruzi, remains the leading cause of cardiopathy in Latin America with about 12 million people infected. Classic clinical manifestations derive from infection of muscle cells leading to progressive cardiomyopathy, while some patients develop megacolon or megaesophagus. A very aggressive clinical course including fulminant meningoencephalitis has been reported in patients who contract Chagas' disease in the background of immunodeficiency. This includes patients with human immunodeficiency virus infection as well as patients receiving immunosuppressive therapy for organ transplant. Currently, only two drugs are approved for the treatment of Chagas' disease, nifurtimox and benznidazole. Both have significant limitations due to common and serious side effects as well as limited availability. A promising group of new drug leads for Chagas' disease is cysteine protease inhibitors targeting cruzain, the major protease of T. cruzi. The inhibitor N-methyl-Pip-F-homoF-vinyl sulfonyl phenyl (N-methyl-Pip-F-hF-VS phi) is in late-stage preclinical development. Therefore, the question arose as to whether protease inhibitors targeting cruzain would have efficacy in Chagas' disease occurring in the background of immunodeficiency. To address this question, we studied the course of infection in recombinase-deficient (Rag1(-/-)) and normal mice infected with T. cruzi. Infections localized to heart and skeletal muscle in untreated normal animals, while untreated Rag1(-/-) mice showed severe infection in all organs and predominantly in liver and spleen. Treatment with the dipeptide N-methyl-Pip-F-hF-VS phi rescued immunodeficient animals from lethal Chagas' infection. The majority (60 to 100%) of inhibitor-treated Rag1(-/-) mice had increased survival, negative PCR, and normal tissues by histopathological examination.
Doyle
Patricia S
PS
Department of Pathology, University of California San Francisco, CA 94121, USA. patricia.doyle-engel@ucsf.edu
Zhou
Yuan M
YM
Engel
Juan C
JC
McKerrow
James H
JH
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D014355:Chagas Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009547:Nifurtimox / Q000494:pharmacology; D009593:Nitroimidazoles / Q000494:pharmacology; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors; D016019:Survival Analysis; D014344:Trypanocidal Agents / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects*
D015853:Cysteine Proteinase Inhibitors; D018398:Homeodomain Proteins; D009593:Nitroimidazoles; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; C064658:RAG-1 protein; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi; D009547:Nifurtimox; C009999:benzonidazole
Parasitol Today. 1999 Mar;15(3):94-9
10322321
PLoS Med. 2007 Jan;4(1):e14
17214506
Mem Inst Oswaldo Cruz. 1999;94 Suppl 1:325-7
10677748
Mem Inst Oswaldo Cruz. 1999;94 Suppl 1:363-5
10677756
Infect Immun. 2000 Sep;68(9):5314-20
10948160
MMWR Morb Mortal Wkly Rep. 2002 Mar 15;51(10):210-2
11922190
J Med Chem. 2002 Jun 20;45(13):2695-707
12061873
Parasitol Res. 2003 Jun;90 Supp 1:S19-39
12811546
Rev Fac Cien Med Univ Nac Cordoba. 2000;57(2):135-62
12934232
Infect Immun. 2004 Oct;72(10):5892-902
15385491
J Protozool. 1982 Nov;29(4):555-60
6816924
J Protozool. 1984 May;31(2):280-3
6381718
Mutagenesis. 1989 Mar;4(2):105-10
2499745
Mol Biochem Parasitol. 1990 Sep-Oct;42(2):175-87
2270100
Mutagenesis. 1993 Nov;8(6):527-32
8133782
J Med Chem. 1995 Aug 18;38(17):3193-6
7650671
Lancet. 1996 Nov 23;348(9039):1407-13
8937280
Brain Pathol. 1997 Jan;7(1):599-611
9034568
Eur J Biochem. 1997 Mar 1;244(2):596-603
9119029
J Cell Sci. 1998 Mar;111 ( Pt 5):597-606
9454733
J Exp Med. 1998 Aug 17;188(4):725-34
9705954
Am J Trop Med Hyg. 1998 Oct;59(4):526-9
9790423
J Infect Dis. 1999 Aug;180(2):480-6
10395865
Mem Inst Oswaldo Cruz. 2005 May;100(3):325-9
16113877
Liver Transpl. 2005 Sep;11(9):1112-6
16123968
Rev Soc Bras Med Trop. 2005;38 Suppl 2:41-5
16482812
Rev Soc Bras Med Trop. 2006 Jan-Feb;39(1):85-8
16501775
Ann Intern Med. 2006 May 16;144(10):724-34
16702588
Hum Exp Toxicol. 2006 Aug;25(8):471-9
16937919
Postgrad Med J. 2006 Dec;82(974):788-98
17148699
Transfusion. 2007 Mar;47(3):540-4
17319837
Medicina (B Aires). 1999;59 Suppl 2:171-5
10668260