Squalene Synthase As a Target for Chagas Disease Therapeutics


Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects eight million individuals, primarily in Latin America. Currently there is no cure for chronic T. cruzi infections. Unlike humans, this parasite use a variety of sterols (e.g. ergosterol, 24-ethyl-cholesta-5,7,22-trien-3 beta ol, and its 22-dihydro analogs), rather than cholesterol in their cell membranes, so inhibiting endogenous sterol biosynthesis is an important therapeutic target. Here, we report the first structure of the parasite's squalene synthase, which catalyzes the first committed step in sterol biosynthesis, as well as the structures of a broad range of squalene synthase inhibitors active against the clinically relevant intracellular stages, opening the way to new approaches to treating this neglected tropical disease.


Vyšlo v časopise: Squalene Synthase As a Target for Chagas Disease Therapeutics. PLoS Pathog 10(5): e32767. doi:10.1371/journal.ppat.1004114
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.ppat.1004114

Souhrn

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects eight million individuals, primarily in Latin America. Currently there is no cure for chronic T. cruzi infections. Unlike humans, this parasite use a variety of sterols (e.g. ergosterol, 24-ethyl-cholesta-5,7,22-trien-3 beta ol, and its 22-dihydro analogs), rather than cholesterol in their cell membranes, so inhibiting endogenous sterol biosynthesis is an important therapeutic target. Here, we report the first structure of the parasite's squalene synthase, which catalyzes the first committed step in sterol biosynthesis, as well as the structures of a broad range of squalene synthase inhibitors active against the clinically relevant intracellular stages, opening the way to new approaches to treating this neglected tropical disease.


Zdroje

1. KobetsT, GrekovI, LipoldovaM (2012) Leishmaniasis: prevention, parasite detection and treatment. Curr Med Chem 19: 1443–1474 doi:10.2174/092986712799828300

2. CDC-Centers for Disease Control and Prevention (2013) Chagas Disease - Epidemiology & Risk Factors. Available at: http://www.cdc.gov/parasites/chagas/epi.html.

3. CDC-Centers for Disease Control and Prevention (2013) Chagas Disease in the Americas. Available at: http://www.cdc.gov/parasites/chagas/resources/chagasdiseaseintheamericas.pdf.

4. LeeBY, BaconKM, BottazziME, HotezPJ (2013) Global economic burden of Chagas disease: a computational simulation model. Lancet Infect Dis 13: 342–348 doi:10.1016/S1473-3099(13)70002-1

5. ClaytonJ (2010) Chagas disease: pushing through the pipeline. Nature 465: S12–S15 doi:10.1038/nature09224

6. MoloneyA (2009) Trial renews interest in Chagas' disease. Lancet 374: 1490.

7. DocampoR, MorenoSNJ, TurrensJF, KatzinAM, Gonzalez-CappaSM, et al. (1981) Biochemical and ultrastructural alterations produced by miconazole and econazole in Trypanosoma cruzi. Mol Biochem Parasitol 3: 169–180 doi:10.1016/0166-6851(81)90047-5

8. MaldonadoRA, MolinaJ, PayaresG, UrbinaJA (1993) Experimental chemotherapy with combinations of ergosterol biosynthesis inhibitors in murine models of Chagas' disease. Antimicrob Agents Chemother 37: 1353–1359 doi:10.1128/AAC.37.6.1353

9. BucknerFS, UrbinaJA (2012) Recent developments in sterol 14-demethylase inhibitors for Chagas disease. Int J Parasitol Drugs Drug Resist 2: 236–242 doi:10.1016/j.ijpddr.2011.12.002

10. MartinMB, ArnoldW, HeathHTIII, UrbinaJA, OldfieldE (1999) Nitrogen-containing bisphosphonates as carbocation transition state analogs for isoprenoid biosynthesis. Biochem Biophys Res Commun 263: 754–758 doi:10.1006/bbrc.1999.1404

11. OldfieldE (2010) Targeting isoprenoid biosynthesis for drug discovery: bench to bedside. Acc Chem Res 43: 1216–1226 doi:10.1021/ar100026v

12. GodefroiEF, HeeresJ, Van CutsemJ, JanssenPAJ (1969) Preparation and antimycotic properties of derivatives of 1-phenethylimidazole. J Med Chem 12: 784–791 doi:10.1021/jm00305a014

13. UrbinaJA, PayaresG, ContrerasLM, LiendoA, SanojaC, et al. (1998) Antiproliferative effects and mechanism of action of SCH 56592 against Trypanosoma (Schizotrypanum) cruzi: in vitro and in vivo studies. Antimicrob Agents Chemother 42: 1771–1777.

14. Okada T, Kurusu N, Tanaka K, Miyazaki K, Shinmyo D, et al., inventors; Eisai Co., Ltd., assignee (2003 Jul 29) Quinuclidine compounds and drugs containing the same as the active ingredient. United States Patent 6,599,917.

15. UrbinaJA, ConcepcionJL, CalderaA, PayaresG, SanojaC, et al. (2004) In vitro and in vivo activities of E5700 and ER-119884, two novel orally active squalene synthase inhibitors, against Trypanosoma cruzi. Antimicrob Agents Chemother 48: 2379–2387 doi:10.1128/AAC.48.7.2379-2387.2004

16. Sealey-CardonaM, CammererS, JonesS, Ruiz-PérezLM, BrunR, et al. (2007) Kinetic characterization of squalene synthase from Trypanosoma cruzi: selective inhibition by quinuclidine derivatives. Antimicrob Agents Chemother 51: 2123–2129 doi:10.1128/AAC.01454-06

17. UrbinaJA, ConcepcionJL, MontalvettiA, RodriguezJB, DocampoR (2003) Mechanism of action of 4-phenoxyphenoxyethyl thiocyanate (WC-9) against Trypanosoma cruzi, the causative agent of Chagas' disease. Antimicrob Agents Chemother 47: 2047–2050 doi:10.1128/AAC.47.6.2047-2050.2003

18. AminD, CornellSA, GustafsonSK, NeedleSJ, UllrichJW, et al. (1992) Bisphosphonates used for the treatment of bone disorders inhibit squalene synthase and cholesterol biosynthesis. J Lipid Res 33: 1657–1663.

19. AminD, CornellSA, PerroneMH, BilderGE (1996) 1-Hydroxy-3-(methylpentylamino)-propylidene-1,1-bisphosphonic acid as a potent inhibitor of squalene synthase. Arzneimittelforschung 46: 759–762.

20. KavanaghKL, GuoK, DunfordJE, WuX, KnappS, et al. (2006) The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Proc Natl Acad Sci 103: 7829–7834 doi:10.1073/pnas.0601643103

21. MukherjeeS, HuangC, GuerraF, WangK, OldfieldE (2009) Thermodynamics of Bisphosphonates Binding to Human Bone: A Two-Site Model. J Am Chem Soc 131: 8374–8375 doi:10.1021/ja902895p

22. ZhangY, CaoR, YinF, HudockMP, GuoR-T, et al. (2009) Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: an X-ray and NMR investigation. J Am Chem Soc 131: 5153–5162 doi:10.1021/ja808285e

23. NoJH, Dossin F deM, ZhangY, LiuY-L, ZhuW, et al. (2012) Lipophilic analogs of zoledronate and risedronate inhibit Plasmodium geranylgeranyl diphosphate synthase (GGPPS) and exhibit potent antimalarial activity. Proc Natl Acad Sci 109: 4058–4063 doi:10.1073/pnas.1118215109

24. ZhangY, ZhuW, LiuY-L, WangH, WangK, et al. (2013) Chemo-immunotherapeutic antimalarials targeting isoprenoid biosynthesis. ACS Med Chem Lett 4: 423–427 doi:10.1021/ml4000436

25. PanditJ, DanleyDE, SchulteGK, MazzalupoS, PaulyTA, et al. (2000) Crystal structure of human squalene synthase, a key enzyme in cholesterol biosynthesis. J Biol Chem 275: 30610–30617 doi:10.1074/jbc.M004132200

26. LiuC-I, LiuGY, SongY, YinF, HenslerME, et al. (2008) A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence. Science 319: 1391–1394 doi:10.1126/science.1153018

27. LinF-Y, LiuC-I, LiuY-L, ZhangY, WangK, et al. (2010) Mechanism of action and inhibition of dehydrosqualene synthase. Proc Natl Acad Sci 107: 21337–21342 doi:10.1073/pnas.1010907107

28. BlaggBSJ, JarstferMB, RogersDH, PoulterCD (2002) Recombinant Squalene Synthase. A Mechanism for the Rearrangement of Presqualene Diphosphate to Squalene. J Am Chem Soc 124: 8846–8853 doi:10.1021/ja020411a

29. LiuCI, JengWY, ChangWJ, ShihMF, KoTP, et al. (2014) Structural insights into the catalytic mechanism of human squalene synthase. Acta Crystallogr D Biol Crystallogr 70: 231–241 doi:10.1107/S1399004713026230

30. SongY, LinF-Y, YinF, HenslerM, Rodrígues PovedaCA, et al. (2009) Phosphonosulfonates are potent, selective inhibitors of dehydrosqualene synthase and staphyloxanthin biosynthesis in Staphylococcus aureus. J Med Chem 52: 976–988 doi:10.1021/jm801023u

31. OldfieldE, LinF-Y (2012) Terpene Biosynthesis: Modularity Rules. Angew Chem Int Ed Engl 51: 1124–1137 doi:10.1002/anie.201103110

32. AaronJA, ChristiansonDW (2010) Trinuclear Metal Clusters in Catalysis by Terpenoid Synthases. Pure Appl Chem Chim Pure Appl 82: 1585–1597 doi:10.1351/PAC-CON-09-09-37

33. ZhouP, TianF, LvF, ShangZ (2009) Geometric characteristics of hydrogen bonds involving sulfur atoms in proteins. Proteins 76: 151–163 doi:10.1002/prot.22327

34. Desiraju GR, Steiner T (2001) The weak hydrogen bond: in structural chemistry and biology. Oxford: Oxford University Press.

35. ZhangY, CaoR, YinF, LinF-Y, WangH, et al. (2010) Lipophilic pyridinium bisphosphonates: potent γδ T cell stimulators. Angew Chem Int Ed 49: 1136–1138 doi:10.1002/anie.200905933

36. MukkamalaD, NoJH, CassLM, ChangT-K, OldfieldE (2008) Bisphosphonate inhibition of a Plasmodium farnesyl diphosphate synthase and a general method for predicting cell-based activity from enzyme data. J Med Chem 51: 7827–7833 doi:10.1021/jm8009074

37. FerellaM, MontalvettiA, RohloffP, MirandaK, FangJ, et al. (2006) A solanesyl-diphosphate synthase Localizes in glycosomes of Trypanosoma cruzi. J Biol Chem 281: 39339–39348 doi:10.1074/jbc.M607451200

38. ZhangY, RaoR (2012) The V-ATPase as a target for antifungal drugs. Curr Protein Pept Sci 13: 134–140.

39. ZhangY-Q, GamarraS, Garcia-EffronG, ParkS, PerlinDS, et al. (2010) Requirement for Ergosterol in V-ATPase Function Underlies Antifungal Activity of Azole Drugs. PLoS Pathog 6: e1000939 doi:10.1371/journal.ppat.1000939

40. UrbinaJA, ConcepcionJL, RangelS, VisbalG, LiraR (2002) Squalene synthase as a chemotherapeutic target in Trypanosoma cruzi and Leishmania mexicana. Mol Biochem Parasitol 125: 35–45.

41. KelleyLA, SternbergMJE (2009) Protein structure prediction on the Web: a case study using the Phyre server. Nat Protoc 4: 363–371 doi:10.1038/nprot.2009.2

42. Pérez-MorenoG, Sealey-CardonaM, Rodrigues-PovedaC, GelbMH, Ruiz-PérezLM, et al. (2012) Endogenous sterol biosynthesis is important for mitochondrial function and cell morphology in procyclic forms of Trypanosoma brucei. Int J Parasitol 42: 975–989 doi:10.1016/j.ijpara.2012.07.012

43. Fernandes RodriguesJC, ConcepcionJL, RodriguesC, CalderaA, UrbinaJA, et al. (2008) In vitro activities of ER-119884 and E5700, two potent squalene synthase inhibitors, against Leishmania amazonensis: antiproliferative, biochemical, and ultrastructural effects. Antimicrob Agents Chemother 52: 4098–4114 doi:10.1128/AAC.01616-07

44. LinF-Y, LiuY-L, LiK, CaoR, ZhuW, et al. (2012) Head-to-head prenyl tranferases: anti-infective drug targets. J Med Chem 55: 4367–4372 doi:10.1021/jm300208p

45. UrbinaJA (2010) New insights in Chagas disease treatment. Drugs Future 35: 409 doi:10.1358/dof.2010.035.05.1484391

46. Veiga-SantosP, BarriasES, SantosJFC, de Barros MoreiraTL, de CarvalhoTMU, et al. (2012) Effects of amiodarone and posaconazole on the growth and ultrastructure of Trypanosoma cruzi. Int J Antimicrob Agents 40: 61–71 doi:10.1016/j.ijantimicag.2012.03.009

47. HallanderHO, DornbuschK, GezeliusL, JacobsonK, KarlssonI (1982) Synergism between aminoglycosides and cephalosporins with antipseudomonal activity: interaction index and killing curve method. Antimicrob Agents Chemother 22: 743–752 doi:10.1128/AAC.22.5.743

48. WebbMR (1992) A continuous spectrophotometric assay for inorganic phosphate and for measuring phosphate release kinetics in biological systems. Proc Natl Acad Sci U S A 89: 4884–4887.

49. BonéGJ, SteinertM (1956) Isotopes incorporated in the nucleic acids of Trypanosoma mega. Nature 178: 308–309 doi:10.1038/178308a0

50. YinF, CaoR, GoddardA, ZhangY, OldfieldE (2006) Enthalpy versus entropy-driven binding of bisphosphonates to farnesyl diphosphate synthase. J Am Chem Soc 128: 3524–3525 doi:10.1021/ja0601639

51. RecherM, BarbozaAP, LiZ-H, GalizziM, Ferrer-CasalM, et al. (2013) Design, synthesis and biological evaluation of sulfur-containing 1,1-bisphosphonic acids as antiparasitic agents. Eur J Med Chem 60: 431–440 doi:10.1016/j.ejmech.2012.12.015

52. BrungerAT (2007) Version 1.2 of the Crystallography and NMR system. Nat Protoc 2: 2728–2733 doi:10.1038/nprot.2007.406

53. SchüttelkopfAW, van AaltenDMF (2004) PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr D Biol Crystallogr 60: 1355–1363 doi:10.1107/S0907444904011679

54. EmsleyP, CowtanK (2004) Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60: 2126–2132 doi:10.1107/S0907444904019158

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