A nonazole CYP51 inhibitor cures Chagas' disease in a mouse model of acute infection.
Chagas' disease, the leading cause of heart failure in Latin America, is caused by the kinetoplastid protozoan Trypanosoma cruzi. The sterols of T. cruzi resemble those of fungi, both in composition and in biosynthesis. Azole inhibitors of sterol 14alpha-demethylase (CYP51) successfully treat fungal infections in humans, and efforts to adapt the success of antifungal azoles posaconazole and ravuconazole as second-use agents for Chagas' disease are under way. However, to address concerns about the use of azoles for Chagas' disease, including drug resistance and cost, the rational design of nonazole CYP51 inhibitors can provide promising alternative drug chemotypes. We report the curative effect of the nonazole CYP51 inhibitor LP10 in an acute mouse model of T. cruzi infection. Mice treated with an oral dose of 40 mg LP10/kg of body weight twice a day (BID) for 30 days, initiated 24 h postinfection, showed no signs of acute disease and had histologically normal tissues after 6 months. A very stringent test of cure showed that 4/5 mice had negative PCR results for T. cruzi, and parasites were amplified by hemoculture in only two treated mice. These results compare favorably with those reported for posaconazole. Electron microscopy and gas chromatography-mass spectrometry (GC-MS) analysis of sterol composition confirmed that treatment with LP10 blocked the 14alpha-demethylation step and induced breakdown of parasite cell membranes, culminating in severe ultrastructural and morphological alterations and death of the clinically relevant amastigote stage of the parasite.
Doyle
Patricia S
PS
Sandler Center for Basic Research in Parasitic Diseases, University of California, San Francisco, CA 54158, USA.
Chen
Chiung-Kuang
CK
Johnston
Jonathan B
JB
Hopkins
Stephanie D
SD
Leung
Siegfried S F
SS
Jacobson
Matthew P
MP
Engel
Juan C
JC
McKerrow
James H
JH
Podust
Larissa M
LM
D000631:Aminopyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013261:Sterols / Q000096:biosynthesis; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology* / Q000648:ultrastructure
D000631:Aminopyridines; D000981:Antiprotozoal Agents; C509352:CYP51 protein, Trypanosoma cruzi; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D013261:Sterols; C552044:alpha-((4-methylcyclohexyl)carbonylamino)-N-4-pyridinyl-1H-indole-3-propanamide; D003577:Cytochrome P-450 Enzyme System
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