Sterculic Acid and Its Analogues Are Potent Inhibitors of Toxoplasma gondii
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Toxoplasmosis is a serious disease caused by Toxoplasma gondii, one of the most widespread parasites in the world. Lipid metabolism is important in the intracellular stage of T. gondii. Stearoyl-CoA desaturase (SCD), a key enzyme for the synthesis of unsaturated fatty acid is predicted to exist in T. gondii. Sterculic acid has been shown to specifically inhibit SCD activity. Here, we examined whether sterculic acid and its methyl ester analogues exhibit anti-T. gondii effects in vitro. T. gondii-infected Vero cells were disintegrated at 36 hr because of the propagation and egress of intracellular tachyzoites. All test compounds inhibited tachyzoite propagation and egress, reducing the number of ruptured Vero cells by the parasites. Sterculic acid and the methyl esters also inhibited replication of intracellular tachyzoites in HFF cells. Among the test compounds, sterculic acid showed the most potent activity against T. gondii, with an EC50 value of 36.2 μM, compared with EC50 values of 248-428 μM for the methyl esters. Our study demonstrated that sterculic acid and its analogues are effective in inhibition of T. gondii growth in vitro, suggesting that these compounds or analogues targeting SCD could be effective agents for the treatment of toxoplasmosis.
Abstract
Toxoplasmosis is a serious disease caused by Toxoplasma gondii, one of the most widespread parasites in the world. Lipid metabolism is important in the intracellular stage of T. gondii. Stearoyl-CoA desaturase (SCD), a key enzyme for the synthesis of unsaturated fatty acid is predicted to exist in T. gondii. Sterculic acid has been shown to specifically inhibit SCD activity. Here, we examined whether sterculic acid and its methyl ester analogues exhibit anti-T. gondii effects in vitro. T. gondii-infected Vero cells were disintegrated at 36 hr because of the propagation and egress of intracellular tachyzoites. All test compounds inhibited tachyzoite propagation and egress, reducing the number of ruptured Vero cells by the parasites. Sterculic acid and the methyl esters also inhibited replication of intracellular tachyzoites in HFF cells. Among the test compounds, sterculic acid showed the most potent activity against T. gondii, with an EC50 value of 36.2 μM, compared with EC50 values of 248-428 μM for the methyl esters. Our study demonstrated that sterculic acid and its analogues are effective in inhibition of T. gondii growth in vitro, suggesting that these compounds or analogues targeting SCD could be effective agents for the treatment of toxoplasmosis.
참고문헌 (20)
- Lüder CG, "Toxoplasmosis: a persisting challenge", Trends Parasitol, 17, pp.460~463 (2001)
- Martins-Duarte ES, "Antiproliferative activities of two novel quinuclidine inhibitors against Toxoplasma gondii tachyzoites in vitro", J Antimicrob Chemother, 58, pp.59~65 (2006)
- Ferra B, "Serodiagnosis of Toxoplasma gondii infection in farm animals (horses, swine, and sheep) by enzyme-linked immunosorbent assay using chimeric antigens", Parasitol Int, 64, pp.288~294 (2015)
- Kavitha N, "In vitro anti-Toxoplasma gondii activity of root extract", fractions of Eurycoma longifolia Jack, 2012, pp.12, 91~
- Jeffcoat R, "Studies on the inhibition of the desaturases by cyclopropenoid fatty acids", Lipids, 12, pp.480~485 (1977)
- Gratraud P, "Oleic acid biosynthesis in Plasmodium falciparum: characterization of the stearoyl-CoA desaturase and investigation as a potential therapeutic target", PLoS One, 4, pp.e6889~ (2009)
- Baird MS, "A new approach to cyclopropene fatty acids", Tetrahedron Lett, 33, pp.1521~1522 (1992)
- Baird MS, "A new approach to cyclopropene fatty acids involving 1,2-deiodination", J Chem Soc Perkin Trans, 1, pp.1547~1548 (1993)
- Weiss LM, "Toxoplasma gondii - the Model Apicomplexan: Perspectives and Methods", pp.594~595 (2014), Academic Press
- Kadegowda AK, "Inhibition of stearoyl-CoA desaturase 1 reduces lipogenesis in primary bovine adipocytes", Lipids, 48, pp.967~976 (2013)
- Scarpelli DG, "Mitogenic activity of sterculic acid, a cyclopropenoid fatty acid", Science, 185, pp.958~960 (1974)
- Leveille AS, "The mitogenic effects of methyl sterculate on aortic smooth muscle cells", Artery, 11, pp.207~224 (1982)
- Gomez FE, "Effects of sterculic acid on stearoyl-CoA desaturase in differentiating 3T3-L1 adipocytes", Biochem Biophys Res Commun, 300, pp.316~326 (2003)
- Waltermann M, "In vitro effects of sterculic acid on lipid biosynthesis in Rhodococcus opacus strain PD630 and isolation of mutants defective in fatty acid desaturation", FEMS Microbiol Lett, 190, pp.45~50 (2000)
- Scaglia N, "Stearoyl-CoA desaturase is involved in the control of proliferation, anchorage-independent growth, and survival in human transformed cells", J Biol Chem, 280, pp.25339~25349 (2005)
- Igal RA, "Stearoyl-CoA desaturase-1: a novel key player in the mechanisms of cell proliferation, programmed cell death and transformation to cancer", Carcinogenesis, 31, pp.1509~1515 (2010)
- Ramakrishnan S, "Apicoplast and endoplasmic reticulum cooperate in fatty acid biosynthesis in apicomplexan parasite Toxoplasma gondii", J Biol Chem, 287, pp.4957~4971 (2012)
- Charron AJ, "Host cells: mobilizable lipid resources for the intracellular parasite Toxoplasma gondii", J Cell Sci, 115, pp.3049~3059 (2002)
- Mazumdar J, "Apicoplast fatty acid synthesis is essential for organelle biogenesis and parasite survival in Toxoplasma gondii", Proc Natl Acad Sci USA, 103, pp.13192~13197 (2006)
- Poloni S, "Stearoyl-CoA Desaturase-1: is it the link between sulfur amino acids and lipid metabolism?", Biology, 4, pp.383~396 (2015)