Invasion and Development of Trypanosoma cruzi in Primary Cultures of Mouse Embryo Hepatocytes

Porrozzi, Renato; Soares, Rodrigo Pedro; Meuser, M. B.

doi:10.1590/s0074-02761997000100025

Cited by 6 publications

(2 citation statements)

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“…Cytotoxicity of compounds was assessed against two different cell types, cardiomyocytes and hepatocytes, isolated from 18-day-old mouse embryos as previously described. , Briefly, to obtain cardiomyocytes, cardiac embryo fragments were dissociated in PBS, supplemented with 0.025% trypsin and 0.01% collagenase (Worthington Co., Lakewood, NJ), and plated in a density of 5 × 10 5 cells/well into a white opaque flat bottom μclear 96-well plate (Greiner Bio-One) coated with 0.01% gelatin. Cultures were maintained in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% FBS, 2.5 mM CaCl 2 , 1 mM l -glutamine, and 2% chicken embryo extract.…”

Section: Methodsmentioning

confidence: 99%

4-Aminopyridyl-Based CYP51 Inhibitors as Anti-Trypanosoma cruzi Drug Leads with Improved Pharmacokinetic Profile and in Vivo Potency

Calvet

Vieira²,

Choi³

et al. 2014

J. Med. Chem.

101

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CYP51 is a P450 enzyme involved in the biosynthesis of the sterol components of eukaryotic cell membranes. CYP51 inhibitors have been developed to treat infections caused by fungi, and more recently the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. To specifically optimize drug candidates for T. cruzi CYP51 (TcCYP51), we explored the structure–activity relationship (SAR) of a N-indolyl-oxopyridinyl-4-aminopropanyl-based scaffold originally identified in a target-based screen. This scaffold evolved via medicinal chemistry to yield orally bioavailable leads with potent anti-T. cruzi activity in vivo. Using an animal model of infection with a transgenic T. cruzi Y luc strain expressing firefly luciferase, we prioritized the biaryl and N-arylpiperazine analogues by oral bioavailability and potency. The drug–target complexes for both scaffold variants were characterized by X-ray structure analysis. Optimization of both binding mode and pharmacokinetic properties of these compounds led to potent inhibitors against experimental T. cruzi infection.

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Section: Methodsmentioning

confidence: 99%

4-Aminopyridyl-Based CYP51 Inhibitors as Anti-Trypanosoma cruzi Drug Leads with Improved Pharmacokinetic Profile and in Vivo Potency

Calvet

Vieira²,

Choi³

et al. 2014

J. Med. Chem.

101

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“…1 Interestingly, hepatocytes in vivo are not commonly observed to be infected, while cultured hepatocytes in vitro are readily infected with trypomastigotes. 3,4 Unlike other forms of liver injury, such as those that result from neoplasm, viral hepatitis or physical injury, and in which cell cycle regulatory genes have been extensively investigated, [5][6][7][8][9][10] the cellular and molecular consequences on the liver of T. cruzi infection remain poorly defined…”

Section: Introductionmentioning

confidence: 99%

Cell Cycle Regulatory Proteins in the Liver in Murine Trypanosoma cruzi Infection

Bouzahzah

Nagajyothi²,

Desruisseaux³

et al. 2006

Cell Cycle

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The liver is an important target of Trypanosoma cruzi infection. Infection of CD-1 mice with T. cruzi (Brazil strain) resulted in parasitism of the liver, primarily in sinusoidal and Kupffer cells. Immunoblot analysis revealed activation of extra cellular signal-regulated kinase (ERK) during the acute and subacute period of infection, but p38 mitogen activated kinase (MAPK) and JNK were not activated. The activity of important cell cycle regulatory genes was also examined in the liver following infection. There was increased expression of cyclin D1, cyclin E and cyclin A as well as proliferating cell nuclear antigen (PCNA) at 45, 60 and 215 days post infection. In addition, the levels of the cyclin-dependent kinase inhibitors p27 KIP1 , p21 WAF1 and the tumor suppressor p53 were increased in the livers obtained from infected mice. Quantitative PCR revealed increased abundance of mRNA for cyclins A, D1 and E. Interestingly, cyclin A and E are ordinarily not found in the adult liver. Thus infection caused a reversion to a fetal/neonatal phenotype. These data provide a molecular basis for cell proliferation in the liver following T. cruzi infection.

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In vitro evidence for metallopeptidase participation in hepatocyte damage induced by Leishmania chagasi-infected macrophages

Costa¹,

Melo²,

Vermelho³

et al. 2008

Acta Tropica

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Invasion and Development of Trypanosoma cruzi in Primary Cultures of Mouse Embryo Hepatocytes

Cited by 6 publications

References 0 publications

4-Aminopyridyl-Based CYP51 Inhibitors as Anti-Trypanosoma cruzi Drug Leads with Improved Pharmacokinetic Profile and in Vivo Potency

4-Aminopyridyl-Based CYP51 Inhibitors as Anti-Trypanosoma cruzi Drug Leads with Improved Pharmacokinetic Profile and in Vivo Potency

Cell Cycle Regulatory Proteins in the Liver in Murine Trypanosoma cruzi Infection

In vitro evidence for metallopeptidase participation in hepatocyte damage induced by Leishmania chagasi-infected macrophages

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