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Treatment of Toxoplasmosis: An Insight on Epigenetic Drugs

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Antiprotozoal Drug Development and Delivery

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 39))

Abstract

Toxoplasmosis is the parasitic infection caused by the obligate intracellular parasite T. gondii. This pathogen possesses three different stages of life, namely (1) sporozoites, (2) tachyzoites (3) and bradyzoites, the slow replicating form living in tissue cysts. To date, the clinical therapy of toxoplasmosis is still based on the use of drugs developed more than 50 years ago and endowed with high toxicity and ineffectiveness against bradyzoites, preventing the complete eradication of the parasite. For these reasons, novel and more effective drugs are still necessary. Epigenetics drugs could fulfil this requirement offering novel mechanisms of action also affecting the bradyzoite stage. Here we report the inhibitors of T. gondii affecting epigenetic targets discovered in the last 25 years.

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References

  1. Ferguson DJP (2009) Toxoplasma gondii: 1908-2008, homage to Nicolle, Manceaux and Splendore. Mem Inst Oswaldo Cruz 104:133–148. https://doi.org/10.1590/S0074-02762009000200003

    Article  PubMed  Google Scholar 

  2. Al-Malki ES (2021) Toxoplasmosis: stages of the protozoan life cycle and risk assessment in humans and animals for an enhanced awareness and an improved socio-economic status. Saudi J Biol Sci 28:962–969

    Article  Google Scholar 

  3. Stanić Ž, Fureš R (2020) Toxoplasmosis: a global zoonosis. Veterinaria 69:31–42

    Google Scholar 

  4. Weiss LM, Dubey JP (2009) Toxoplasmosis: a history of clinical observations. Int J Parasitol 39:895–901. https://doi.org/10.1016/j.ijpara.2009.02.004

    Article  PubMed  PubMed Central  Google Scholar 

  5. Elsheikha HM, Marra CM, Zhu X-Q (2020) Epidemiology, pathophysiology, diagnosis, and management of cerebral toxoplasmosis. Clin Microbiol Rev 34:1–28. https://doi.org/10.1128/CMR.00115-19

    Article  Google Scholar 

  6. Halonen SK, Weiss LM (2013) Toxoplasmosis. In. Handb Clin Neurol 114:125–145

    Article  Google Scholar 

  7. Di Genova BM, Wilson SK, Dubey JP, Knoll LJ (2019) Intestinal delta-6-desaturase activity determines host range for Toxoplasma sexual reproduction. bioRxiv:1–19. https://doi.org/10.1101/688580

  8. Blader IJ, Coleman BI, Chen CT, Gubbels MJ (2015) Lytic cycle of Toxoplasma gondii: 15 years later. Annu Rev Microbiol 69:463–485

    Article  CAS  Google Scholar 

  9. Wang ZD, Liu HH, Ma ZX, Ma HY, Li ZY, Yang ZB, Zhu XQ, Xu B, Wei F, Liu Q (2017) Toxoplasma gondii infection in immunocompromised patients: a systematic review and meta-analysis. Front Microbiol 8:1–12. https://doi.org/10.3389/fmicb.2017.00389

    Article  Google Scholar 

  10. Cerutti A, Blanchard N, Besteiro S (2020) The bradyzoite: a key developmental stage for the persistence and pathogenesis of toxoplasmosis. Pathogens 9:1–21

    Article  Google Scholar 

  11. Hill D, Dubey JP (2002) Toxoplasma gondii: transmission, diagnosis, and prevention. Clin Microbiol Infect 8:634–640. https://doi.org/10.1046/j.1469-0691.2002.00485.x

    Article  CAS  PubMed  Google Scholar 

  12. Dubey JP (2004) Toxoplasmosis - a waterborne zoonosis. Vet Parasitol 126:57–72. https://doi.org/10.1016/j.vetpar.2004.09.005

    Article  CAS  PubMed  Google Scholar 

  13. Johnson SK, Johnson PTJ (2021) Toxoplasmosis: recent advances in understanding the link between infection and host behavior. Annu Rev Anim Biosci 9:249–264

    Article  Google Scholar 

  14. McAuley JB (2014) Congenital toxoplasmosis. J Pediatr Infect Dis Soc 3:30–35. https://doi.org/10.1093/jpids/piu077

    Article  Google Scholar 

  15. Demar M, Hommel D, Djossou F, Peneau C, Boukhari R, Louvel D, Bourbigot AM, Nasser V, Ajzenberg D, Darde ML et al (2012) Acute toxoplasmoses in immunocompetent patients hospitalized in an intensive care unit in French Guiana. Clin Microbiol Infect 18:E221–E231. https://doi.org/10.1111/j.1469-0691.2011.03648.x

    Article  CAS  PubMed  Google Scholar 

  16. Oz HS (2014) Maternal and congenital toxoplasmosis, currently available and novel therapies in horizon. Front Microbiol 5:1–6. https://doi.org/10.3389/fmicb.2014.00385

    Article  Google Scholar 

  17. Montoya JG, Remington JS (2008) Management of Toxoplasma gondii infection during pregnancy. Clin Infect Dis 47:554–566. https://doi.org/10.1086/590149

    Article  PubMed  Google Scholar 

  18. Demar M, Ajzenberg D, Maubon D, Djossou F, Panchoe D, Punwasi W, Valery N, Peneau C, Daigre JL, Aznar C et al (2007) Fatal outbreak of human toxoplasmosis along the Maroni River: epidemiological, clinical, and parasitological aspects. Clin Infect Dis 45. https://doi.org/10.1086/521246

  19. Sabin AB, Warren J (1942) Therapeutic effectiveness of certain sulfonamides on infection by an intracellular protozoon (toxoplasma). Proc Soc Exp Biol Med 51:19–23. https://doi.org/10.3181/00379727-51-13809

    Article  CAS  Google Scholar 

  20. Eyles DE, Coleman N (1953) Synergistic effect of sulfadiazlne and daraprim against experimental toxoplasmosis in the mouse. Antibiot Chemother 3:483–490

    CAS  Google Scholar 

  21. Konstantinovic N, Guegan H, Stäjner T, Belaz S, Robert-Gangneux F (2019) Treatment of toxoplasmosis: current options and future perspectives. Food Waterborne Parasitol 15. https://doi.org/10.1016/j.fawpar.2019.e00036

  22. Wettingfeld RF, Rowe J, Eyles DE (1956) Treatment of toxoplasmosis with pyrimethamine (daraprim) and triple sulfonamide. Ann Intern Med 44:557–564. https://doi.org/10.7326/0003-4819-44-3-557

    Article  CAS  PubMed  Google Scholar 

  23. Kayhoe DE, Jacobs L, Beye HK, McCullough NB (1957) Acquired toxoplasmosis; observations on two parasitologically proved cases treated with pyrimethamine and triple sulfonamides. N Engl J Med 257:1247–1254. https://doi.org/10.1056/NEJM195712262572601

    Article  CAS  PubMed  Google Scholar 

  24. Dunay IR, Gajurel K, Dhakal R, Liesenfeld O, Montoya JG (2018) Treatment of toxoplasmosis: historical perspective, animal models, and current clinical practice. Clin Microbiol Rev 31:1–33

    Article  Google Scholar 

  25. Kovacs JA, Allegra CJ, Beaver J, Boarman D, Lewis M, Parrillo JE, Chabner B, Masur H (1989) Characterization of de novo folate synthesis in Pneumocystis carinii and Toxoplasma gondii: potential for screening therapeutic agents. J Infect Dis 160:312–320. https://doi.org/10.1093/infdis/160.2.312

    Article  CAS  PubMed  Google Scholar 

  26. Pfefferkorn ER, Nothnagel RF, Borotz SE (1992) Parasiticidal effect of clindamycin on Toxoplasma gondii grown in cultured cells and selection of a drug-resistant mutant. Antimicrob Agents Chemother 36:1091–1096. https://doi.org/10.1128/AAC.36.5.1091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Blais J, Tardif C, Chamberland S (1993) Effect of clindamycin on intracellular replication, protein synthesis, and infectivity of Toxoplasma gondii. Antimicrob Agents Chemother 37:2571–2577. https://doi.org/10.1128/AAC.37.12.2571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Camps M, Arrizabalaga G, Boothroyd J (2002) An rRNA mutation identifies the apicoplast as the target for clindamycin in Toxoplasma gondii. Mol Microbiol 43:1309–1318. https://doi.org/10.1046/j.1365-2958.2002.02825.x

    Article  CAS  PubMed  Google Scholar 

  29. Chang HR, Pechere JCF (1988) Activity of spiramycin against Toxoplasma gondii in vitro, in experimental infections and in human infection. J Antimicrob Chemother 22:87–92. https://doi.org/10.1093/jac/22.supplement_b.87

    Article  CAS  PubMed  Google Scholar 

  30. Alday PH, Doggett JS (2017) Drugs in development for toxoplasmosis: advances, challenges, and current status. Drug Des Devel Ther 11:273–293. https://doi.org/10.2147/DDDT.S60973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ram EVSR, Naik R, Ganguli M, Habib S (2008) DNA organization by the apicoplast-targeted bacterial histone-like protein of Plasmodium falciparum. Nucleic Acids Res 36:5061–5073. https://doi.org/10.1093/nar/gkn483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Reiff SB, Vaishnava S, Striepena B (2012) The HU protein is important for apicoplast genome maintenance and inheritance in Toxoplasma gondii. Eukaryot Cell 11:905–915. https://doi.org/10.1128/EC.00029-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dannemann B, McCutchan JA, Israelski D, Antoniskis D, Leport C, Luft B, Nussbaum J, Clumeck N, Morlat P, Chiu J et al (1992) Treatment of toxoplasmic encephalitis in patients with AIDS: a randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. Ann Intern Med 116:33–43. https://doi.org/10.7326/0003-4819-116-1-33

    Article  CAS  PubMed  Google Scholar 

  34. Katlama C, De Wit S, O’Doherty E, Van Glabeke M, Clumeck N (1996) Pyrimethamine-clindamycin vs. pyrimethamine-sulfadiazine as acute and long-term therapy for toxoplasmic encephalitis in patients with AIDS. Clin Infect Dis 22:268–275. https://doi.org/10.1093/clinids/22.2.268

    Article  CAS  PubMed  Google Scholar 

  35. Fernandez-Martin J, Leport C, Morlat P, Meyohas MC, Chauvin JP, Vilde JL (1991) Pyrimethamine-clarithromycin combination for therapy of acute toxoplasma encephalitis in patients with AIDS. Antimicrob Agents Chemother 35:2049–2052. https://doi.org/10.1128/AAC.35.10.2049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Shiojiri D, Kinai E, Teruya K, Kikuchi Y, Oka S (2019) Combination of clindamycin and azithromycin as alternative treatment for Toxoplasma gondii encephalitis. Emerg Infect Dis 25:841–843

    Article  CAS  Google Scholar 

  37. Torres RA, Weinberg W, Stansell J, Leoung G, Kovacs J, Rogers M, Scott J (1997) Atovaquone for salvage treatment and suppression of toxoplasmic encephalitis in patients with AIDS. Clin Infect Dis 24:422–429. https://doi.org/10.1093/clinids/24.3.422

    Article  CAS  PubMed  Google Scholar 

  38. Araujo FG, Shepard RM, Remington JS (1991) In vivo activity of the macrolide antibiotics azithromycin, roxithromycin and spiramycin against Toxoplasma gondii. Eur J Clin Microbiol Infect Dis 10:519–524. https://doi.org/10.1007/BF01963942

    Article  CAS  PubMed  Google Scholar 

  39. Couvreur J, Desmonts G, Thulliez P (1988) Prophylaxis of congenital toxoplasmosis. Effects of spiramycin on placental infection. J Antimicrob Chemother 22:193–200. https://doi.org/10.1093/jac/22.Supplement_B.193

    Article  PubMed  Google Scholar 

  40. Angel SO, Vanagas L, Ruiz DM, Cristaldi C, Saldarriaga Cartagena AM, Sullivan WJ (2020) Emerging therapeutic targets against Toxoplasma gondii: update on DNA repair response inhibitors and genotoxic drugs. Front Cell Infect Microbiol 10:1–15. https://doi.org/10.3389/fcimb.2020.00289

    Article  CAS  Google Scholar 

  41. McFarland MM, Zach SJ, Wang X, Potluri LP, Neville AJ, Vennerstrom JL, Davis PH (2016) Review of experimental compounds demonstrating anti-toxoplasma activity. Antimicrob Agents Chemother 60:7017–7034. https://doi.org/10.1128/AAC.01176-16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Do HH, Van Le Q, Tekalgne MA, Tran AV, Lee TH, Hong SH, Han SM, Ahn SH, Kim YJ, Jang HW et al (2021) Metal–organic framework-derived MoSx composites as efficient electrocatalysts for hydrogen evolution reaction. J Alloys Compd 852:156952. https://doi.org/10.1016/j.jallcom.2020.156952

    Article  CAS  Google Scholar 

  43. Rocha-Roa C, Molina D, Cardona N (2018) A perspective on thiazolidinone scaffold development as a new therapeutic strategy for toxoplasmosis. Front Cell Infect Microbiol 8:1–8

    Article  Google Scholar 

  44. Montazeri M, Sharif M, Sarvi S, Mehrzadi S, Ahmadpour E, Daryani A (2017) A systematic review of in vitro and in vivo activities of anti-toxoplasma drugs and compounds (2006-2016). Front Microbiol 8:25

    PubMed  PubMed Central  Google Scholar 

  45. Carradori S, Secci D, Bizzarri B, Chimenti P, De Monte C, Guglielmi P, Campestre C, Rivanera D, Bordón C, Jones-Brando L (2017) Synthesis and biological evaluation of anti-Toxoplasma gondii activity of a novel scaffold of thiazolidinone derivatives. J Enzyme Inhib Med Chem 32:746–758. https://doi.org/10.1080/14756366.2017.1316494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Deng Y, Wu T, Zhai SQ, Li CH (2019) Recent progress on anti-toxoplasma drugs discovery: design, synthesis and screening. Eur J Med Chem 183:111711. https://doi.org/10.1016/j.ejmech.2019.111711

    Article  CAS  PubMed  Google Scholar 

  47. Rutaganira FU, Barks J, Dhason MS, Wang Q, Lopez MS, Long S, Radke JB, Jones NG, Maddirala AR, Janetka JW et al (2017) Inhibition of calcium dependent protein kinase 1 (CDPK1) by pyrazolopyrimidine analogs decreases establishment and reoccurrence of central nervous system disease by Toxoplasma gondii. J Med Chem 60:9976–9989. https://doi.org/10.1021/acs.jmedchem.7b01192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Vidadala RSR, Rivas KL, Ojo KK, Hulverson MA, Zambriski JA, Bruzual I, Schultz TL, Huang W, Zhang Z, Scheele S et al (2016) Development of an orally available and central nervous system (CNS) penetrant Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) inhibitor with minimal human ether-a-go-go-related gene (hERG) activity for the treatment of toxoplasmosis. J Med Chem 59:6531–6546. https://doi.org/10.1021/acs.jmedchem.6b00760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hulverson MA, Bruzual I, Mcconnell EV, Huang W, Vidadala RSR, Choi R, Arnold SLM, Whitman GR, Mccloskey MC, Barrett LK et al (2019) Pharmacokinetics and in vivo efficacy of pyrazolopyrimidine, pyrrolopyrimidine, and 5-aminopyrazole-4-carboxamide bumped kinase inhibitors against toxoplasmosis. J Infect Dis 219:1464–1473. https://doi.org/10.1093/infdis/jiy664

    Article  CAS  PubMed  Google Scholar 

  50. Moine E, Moiré N, Dimier-Poisson I, Brunet K, Couet W, Colas C, Van Langendonck N, Enguehard-Gueiffier C, Gueiffier A, Héraut B et al (2018) Imidazo[1,2-b]pyridazines targeting Toxoplasma gondii calcium-dependent protein kinase 1 decrease the parasite burden in mice with acute toxoplasmosis. Int J Parasitol 48:561–568. https://doi.org/10.1016/j.ijpara.2017.12.006

    Article  CAS  PubMed  Google Scholar 

  51. Janetka JW, Hopper AT, Yang Z, Barks J, Dhason MS, Wang Q, Sibley LD (2020) Optimizing pyrazolopyrimidine inhibitors of calcium dependent protein kinase 1 for treatment of acute and chronic toxoplasmosis. J Med Chem 63:6144–6163. https://doi.org/10.1021/acs.jmedchem.0c00419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Roos DS (1993) Primary structure of the dihydrofolate reductase-thymidylate synthase gene from Toxoplasma gondii. J Biol Chem 268:6269–6280. https://doi.org/10.1016/s0021-9258(18)53249-x

    Article  CAS  PubMed  Google Scholar 

  53. Donald RGK, Roos DS (1994) Homologous recombination and gene replacement at the dihydrofolate reductase-thymidylate synthase locus in Toxoplasma gondii. Mol Biochem Parasitol 63:243–253. https://doi.org/10.1016/0166-6851(94)90060-4

    Article  CAS  PubMed  Google Scholar 

  54. Zaware N, Sharma H, Yang J, Devambatla RKV, Queener SF, Anderson KS, Gangjee A (2013) Discovery of potent and selective inhibitors of Toxoplasma gondii thymidylate synthase for opportunistic infections. ACS Med Chem Lett 4:1148–1151. https://doi.org/10.1021/ml400208v

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hopper AT, Brockman A, Wise A, Gould J, Barks J, Radke JB, Sibley LD, Zou Y, Thomas S (2019) Discovery of selective Toxoplasma gondii dihydrofolate reductase inhibitors for the treatment of toxoplasmosis. J Med Chem 62:1562–1576. https://doi.org/10.1021/acs.jmedchem.8b01754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Welsch ME, Zhou J, Gao Y, Yan Y, Porter G, Agnihotri G, Li Y, Lu H, Chen Z, Thomas SB (2016) Discovery of potent and selective leads against Toxoplasma gondii dihydrofolate reductase via structure-based design. ACS Med Chem Lett 7:1124–1129. https://doi.org/10.1021/acsmedchemlett.6b00328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Larson ET, Parussini F, Huynh MH, Giebel JD, Kelley AM, Zhang L, Bogyo M, Merritt EA, Carruthers VB (2009) Toxoplasma gondii cathepsin L is the primary target of the invasion-inhibitory compound morpholinurea-leucylhomophenyl-vinyl sulfone phenyl. J Biol Chem 284:26839–26850. https://doi.org/10.1074/jbc.M109.003780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zwicker JD, Diaz NA, Guerra AJ, Kirchhoff PD, Wen B, Sun D, Carruthers VB, Larsen SD (2018) Optimization of dipeptidic inhibitors of cathepsin L for improved Toxoplasma gondii selectivity and CNS permeability. Bioorganic Med Chem Lett 28:1972–1980. https://doi.org/10.1016/j.bmcl.2018.03.020

    Article  CAS  Google Scholar 

  59. Szajnman SH, Galaka T, Li ZH, Li C, Howell NM, Chao MN, Striepen B, Muralidharan V, Moreno SNJ, Rodriguez JB (2017) In vitro and in vivo activities of sulfur-containing linear bisphosphonates against apicomplexan parasites. Antimicrob Agents Chemother 61:1–10. https://doi.org/10.1128/AAC.01590-16

    Article  Google Scholar 

  60. Recher M, Barboza AP, Li ZH, Galizzi M, Ferrer-Casal M, Szajnman SH, Docampo R, Moreno SNJ, Rodriguez JB (2013) Design, synthesis and biological evaluation of sulfur-containing 1,1-bisphosphonic acids as antiparasitic agents. Eur J Med Chem 60:431–440. https://doi.org/10.1016/j.ejmech.2012.12.015

    Article  CAS  PubMed  Google Scholar 

  61. Zwicker JD, Smith D, Guerra AJ, Hitchens JR, Haug N, Vander Roest S, Lee P, Wen B, Sun D, Wang L et al (2020) Discovery and optimization of triazine nitrile inhibitors of Toxoplasma gondii cathepsin L for the potential treatment of chronic toxoplasmosis in the CNS. ACS Chem Neurosci 11:2450–2463. https://doi.org/10.1021/acschemneuro.9b00674

    Article  CAS  PubMed  Google Scholar 

  62. Galaka T, Falcone BN, Li C, Szajnman SH, Moreno SNJ, Docampo R, Rodriguez JB (2019) Synthesis and biological evaluation of 1-alkylaminomethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii. Bioorganic Med Chem 27:3663–3673. https://doi.org/10.1016/j.bmc.2019.07.004

    Article  CAS  Google Scholar 

  63. Li H, Sadiq MM, Suzuki K, Falcaro P, Hill AJ, Hill MR (2017) Magnetic induction framework synthesis: a general route to the controlled growth of metal-organic frameworks. Chem Mater 29:6186–6190. https://doi.org/10.1021/acs.chemmater.7b01803

    Article  CAS  Google Scholar 

  64. MacLean AE, Bridges HR, Silva MF, Ding S, Ovciarikova J, Hirst J, Sheiner L (2021) Complexome profile of Toxoplasma gondii mitochondria identifies divergent subunits of respiratory chain complexes including new subunits of cytochrome bc1 complex. PLoS Pathog 17:e1009301

    Article  CAS  Google Scholar 

  65. McConnell EV, Bruzual I, Pou S, Winter R, Dodean RA, Smilkstein MJ, Krollenbrock A, Nilsen A, Zakharov LN, Riscoe MK et al (2018) Targeted structure-activity analysis of endochin-like quinolones reveals potent Qi and Qo site inhibitors of Toxoplasma gondii and plasmodium falciparum cytochrome bc1 and identifies ELQ-400 as a remarkably effective compound against acute experimental toxoplasmosis. ACS Infect Dis 4:1574–1584. https://doi.org/10.1021/acsinfecdis.8b00133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Doggett JS, Nilsen A, Forquer I, Wegmann KW, Jones-Brando L, Yolken RH, Bordón C, Charman SA, Katneni K, Schultz T et al (2012) Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis. Proc Natl Acad Sci U S A 109:15936–15941. https://doi.org/10.1073/pnas.1208069109

    Article  PubMed  PubMed Central  Google Scholar 

  67. Stec J, Fomovska A, Afanador GA, Muench SP, Zhou Y, Lai BS, El Bissati K, Hickman MR, Lee PJ, Leed SE et al (2013) Modification of triclosan scaffold in search of improved inhibitors for enoyl-acyl carrier protein (ACP) reductase in Toxoplasma gondii. ChemMedChem 8:1138–1160. https://doi.org/10.1002/cmdc.201300050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Muench SP, Stec J, Zhou Y, Afanador GA, McPhillie MJ, Hickman MR, Lee PJ, Leed SE, Auschwitz JM, Prigge ST et al (2013) Development of a triclosan scaffold which allows for adaptations on both the A- and B-ring for transport peptides. Bioorganic Med Chem Lett 23:3551–3555. https://doi.org/10.1016/j.bmcl.2013.04.035

    Article  CAS  Google Scholar 

  69. Darkin-Rattray SJ, Gurnett AM, Myers RW, Dulski PM, Crumley TM, Allocco JJ, Cannova C, Meinke PT, Colletti SL, Bednarek MA et al (1996) Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase (cyclic tetrapeptide A picomplex a antiparasitic malaria coccidiosis). Med Sci 93:13143–13147

    CAS  Google Scholar 

  70. Dixon SE, Stilger KL, Elias EV, Naguleswaran A, Sullivan WJ (2010) A decade of epigenetic research in Toxoplasma gondii. Mol Biochem Parasitol 173:1–9. https://doi.org/10.1016/j.molbiopara.2010.05.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sullivan WJ, Smith CK (2000) Cloning and characterization of a novel histone acetyltransferase homologue from the protozoan parasite Toxoplasma gondii reveals a distinct GCN5 family member. Gene 242:193–200. https://doi.org/10.1016/S0378-1119(99)00526-0

    Article  CAS  PubMed  Google Scholar 

  72. Hettmann C, Soldati D (1999) Cloning and analysis of a Toxoplasma gondii histone acetyltransferase: a novel chromatin remodelling factor in apicomplexan parasites. Nucleic Acids Res 27:4344–4352. https://doi.org/10.1093/nar/27.22.4344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Smith AT, Tucker-Samaras SD, Fairlamb AH, Sullivan WJ (2005) MYST family histone acetyltransferases in the protozoan parasite Toxoplasma gondii. Eukaryot Cell 4:2057–2065. https://doi.org/10.1128/EC.4.12.2057-2065.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Saksouk N, Bhatti MM, Kieffer S, Smith AT, Musset K, Garin J, Sullivan WJ, Cesbron-Delauw M-F, Hakimi M-A (2005) Histone-modifying complexes regulate gene expression pertinent to the differentiation of the protozoan parasite Toxoplasma gondii. Mol Cell Biol 25:10301–10314. https://doi.org/10.1128/mcb.25.23.10301-10314.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Jeffers V, Yang C, Huang S, Sullivan WJ (2017) Bromodomains in protozoan parasites: evolution, function, and opportunities for drug development. Microbiol Mol Biol Rev 81:1–17. https://doi.org/10.1128/mmbr.00047-16

    Article  CAS  Google Scholar 

  76. Dalmasso MC, Onyango DO, Naguleswaran A, Sullivan WJ, Angel SO (2009) Toxoplasma H2A variants reveal novel insights into nucleosome composition and functions for this histone family. J Mol Biol 392:33–47. https://doi.org/10.1016/j.jmb.2009.07.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Fiorentino F, Mai A, Rotili D (2020) Lysine acetyltransferase inhibitors from natural sources. Front Pharmacol 11:1–15

    Article  Google Scholar 

  78. Jenuwein T, Allis CD (2001) Translating the histone code. Science 293:1074–1080. https://doi.org/10.1126/science.1063127

    Article  CAS  PubMed  Google Scholar 

  79. Park SY, Kim JS (2020) A short guide to histone deacetylases including recent progress on class II enzymes. Exp Mol Med 52:204–212

    Article  CAS  Google Scholar 

  80. Hailu GS, Robaa D, Forgione M, Sippl W, Rotili D, Mai A (2017) Lysine deacetylase inhibitors in parasites: past, present, and future perspectives. J Med Chem 60:4780–4804. https://doi.org/10.1021/acs.jmedchem.6b01595

    Article  CAS  PubMed  Google Scholar 

  81. Kim K (2018) The epigenome, cell cycle, and development in toxoplasma. Annu Rev Microbiol 72:479–499. https://doi.org/10.1146/annurev-micro-090817-062741

    Article  CAS  PubMed  Google Scholar 

  82. Carret K, Duraisingh MT, Voss TS, Ralph SA, Hommel M, Tonkin CJ, Duffy MF, Mancio L, Scherf A, Ivens A et al (2009) Sir2 paralogues cooperate to regulate virulence genes and antigenic variation in plasmodium falciparum. PLoS Biol 7. https://doi.org/10.1371/journal.pbio.1000084

  83. Bhatti MM, Livingston M, Mullapudi N, Sullivan WJ (2006) Pair of unusual GCN5 histone acetyltransferases and ADA2 homologues in the protozoan parasite Toxoplasma gondii. Eukaryot Cell 5:62–76. https://doi.org/10.1128/EC.5.1.62-76.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang J, Dixon SE, Ting LM, Liu TK, Jeffers V, Croken MM, Calloway M, Cannella D, Ali Hakimi M, Kim K et al (2014) Lysine acetyltransferase GCN5b interacts with AP2 factors and is required for Toxoplasma gondii proliferation. PLoS Pathog 10. https://doi.org/10.1371/journal.ppat.1003830

  85. Harris MT, Jeffers V, Martynowicz J, True JD, Mosley AL, Sullivan WJ (2019) A novel GCN5b lysine acetyltransferase complex associates with distinct transcription factors in the protozoan parasite Toxoplasma gondii. Mol Biochem Parasitol 232. https://doi.org/10.1016/j.molbiopara.2019.111203

  86. Naguleswaran A, Elias EV, McClintick J, Edenberg HJ, Sullivan WJ (2010) Toxoplasma gondii lysine acetyltransferase GCN5-a functions in the cellular response to alkaline stress and expression of cyst genes. PLoS Pathog 6:1–10. https://doi.org/10.1371/journal.ppat.1001232

    Article  CAS  Google Scholar 

  87. Kijima M, Yoshida M, Sugita K, Horinouchi S, Beppu T (1993) Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase. J Biol Chem 268:22429–22435. https://doi.org/10.1016/s0021-9258(18)41547-5

    Article  CAS  PubMed  Google Scholar 

  88. Porter NJ, Christianson DW (2017) Binding of the microbial cyclic tetrapeptide trapoxin a to the class i histone deacetylase HDAC8. ACS Chem Biol 12:2281–2286. https://doi.org/10.1021/acschembio.7b00330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hai Y, Christianson DW (2016) Histone deacetylase 6 structure and molecular basis of catalysis and inhibition. Nat Chem Biol 12:741–747. https://doi.org/10.1038/nchembio.2134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Bougdour A, Maubon D, Baldacci P, Ortet P, Bastien O, Bouillon A, Barale JC, Pelloux H, Ménard R, Hakimi MA (2009) Drug inhibition of HDAC3 and epigenetic control of differentiation in Apicomplexa parasites. J Exp Med 206:953–966. https://doi.org/10.1084/jem.20082826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Maubon D, Bougdour A, Wong YS, Brenier-Pinchart MP, Curt A, Hakimi MA, Pelloux H (2010) Activity of the histone deacetylase inhibitor FR235222 on Toxoplasma gondii: inhibition of stage conversion of the parasite cyst form and study of new derivative compounds. Antimicrob Agents Chemother 54:4843–4850. https://doi.org/10.1128/AAC.00462-10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Dubey R, Harrison B, Dangoudoubiyam S, Bandini G, Cheng K, Kosber A, Agop-Nersesian C, Howe DK, Samuelson J, Ferguson DJP et al (2017) Differential roles for inner membrane complex proteins across Toxoplasma gondii and Sarcocystis neurona development. mSphere 2:1–19. https://doi.org/10.1128/msphere.00409-17

    Article  CAS  Google Scholar 

  93. Torrey EF, Yolken RH (2003) Toxoplasma gondii and schizophrenia. Emerg Infect Dis 9:1375–1380. https://doi.org/10.3201/eid0911.030143

    Article  PubMed  PubMed Central  Google Scholar 

  94. Fuglewicz AJ, Piotrowski P, Stodolak A (2017) Relationship between toxoplasmosis and schizophrenia: a review. Adv Clin Exp Med 26:1033–1038. https://doi.org/10.17219/acem/61435

    Article  Google Scholar 

  95. Sutterland AL, Fond G, Kuin A, Koeter MWJ, Lutter R, van Gool T, Yolken R, Szoke A, Leboyer M, de Haan L (2015) Beyond the association. Toxoplasma gondii in schizophrenia, bipolar disorder, and addiction: systematic review and meta-analysis. Acta Psychiatr Scand 132:161–179. https://doi.org/10.1111/acps.12423

    Article  CAS  PubMed  Google Scholar 

  96. Jones-Brando L, Torrey EF, Yolken R (2003) Drugs used in the treatment of schizophrenia and bipolar disorder inhibit the replication of Toxoplasma gondii. Schizophr Res 62:237–244. https://doi.org/10.1016/S0920-9964(02)00357-2

    Article  PubMed  Google Scholar 

  97. Norrby R, Eilard T, Svedhem A, Lycke E (1975) Treatment of toxoplasmosis with trimethoprim-sulphamethoxazole. Scand J Infect Dis 7:72–75. https://doi.org/10.3109/inf.1975.7.issue-1.13

    Article  CAS  PubMed  Google Scholar 

  98. Kuendgen A, Schmid M, Schlenk R, Knipp S, Hildebrandt B, Steidl C, Germing U, Haas R, Dohner H, Gattermann N (2006) The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia. Cancer 106:112–119. https://doi.org/10.1002/cncr.21552

    Article  CAS  PubMed  Google Scholar 

  99. Strobl JS, Cassell M, Mitchell SM, Reilly CM, Lindsay DS (2007) Scriptaid and suberoylanilide hydroxamic acid are histone deacetylase inhibitors with potent anti-Toxoplasma gondii activity in vitro. J Parasitol 93:694–700. https://doi.org/10.1645/GE-1043R.1

    Article  CAS  PubMed  Google Scholar 

  100. Sharma V, Koul N, Joseph C, Dixit D, Ghosh S, Sen E (2010) HDAC inhibitor, scriptaid, induces glioma cell apoptosis through JNK activation and inhibits telomerase activity. J Cell Mol Med 14:2151–2161. https://doi.org/10.1111/j.1582-4934.2009.00844.x

    Article  CAS  PubMed  Google Scholar 

  101. Marks PA (2007) Discovery and development of SAHA as an anticancer agent. Oncogene 26:1351–1356. https://doi.org/10.1038/sj.onc.1210204

    Article  CAS  PubMed  Google Scholar 

  102. Zhao Y, Yu D, Wu H, Liu H, Zhou H, Gu R, Zhang R, Zhang S, Wu G (2014) Anticancer activity of SAHA, a potent histone deacetylase inhibitor, in NCI-H460 human large-cell lung carcinoma cells in vitro and in vivo. Int J Oncol 44:451–458. https://doi.org/10.3892/ijo.2013.2193

    Article  CAS  PubMed  Google Scholar 

  103. Murakoshi F, Bando H, Sugi T, Adeyemi OS, Nonaka M, Nakaya T, Kato K (2020) Nullscript inhibits cryptosporidium and toxoplasma growth. Int J Parasitol Drugs Drug Resist 14:159–166. https://doi.org/10.1016/j.ijpddr.2020.10.004

    Article  PubMed  PubMed Central  Google Scholar 

  104. McFadden DC, Seeber F, Boothroyd JC (1997) Use of Toxoplasma gondii expressing β-galactosidase for colorimetric assessment of drug activity in vitro. Antimicrob Agents Chemother 41:1849–1853. https://doi.org/10.1128/aac.41.9.1849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Araujo-Silva CA, De Souza W, Martins-Duarte ES, Vommaro RC (2021) HDAC inhibitors Tubastatin A and SAHA affect parasite cell division and are potential anti-Toxoplasma gondii chemotherapeutics. Int J Parasitol Drugs Drug Resist 15:25–35. https://doi.org/10.1016/j.ijpddr.2020.12.003

    Article  CAS  PubMed  Google Scholar 

  106. Butler KV, Kalin J, Brochier C, Vistoli G, Langley B, Kozikowski AP (2010) Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A. J Am Chem Soc 132:10842–10846. https://doi.org/10.1021/ja102758v

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Shen S, Svoboda M, Zhang G, Cavasin MA, Motlova L, McKinsey TA, Eubanks JH, Bařinka C, Kozikowski AP (2020) Structural and in vivo characterization of Tubastatin A, a widely used histone deacetylase 6 inhibitor. ACS Med Chem Lett 11:706–712. https://doi.org/10.1021/acsmedchemlett.9b00560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Li ZY, Zhang C, Zhang Y, Chen L, Chen BD, Li QZ, Zhang XJ, Li WP (2017) A novel HDAC6 inhibitor Tubastatin a: controls HDAC6-p97/VCP-mediated ubiquitination-autophagy turnover and reverses Temozolomide-induced ER stress-tolerance in GBM cells. Cancer Lett 391:89–99. https://doi.org/10.1016/j.canlet.2017.01.025

    Article  CAS  PubMed  Google Scholar 

  109. Urdiciain A, Erausquin E, Meléndez B, Rey JA, Idoate MA, Castresana JS (2019) Tubastatin A, an inhibitor of HDAC6, enhances temozolomide-induced apoptosis and reverses the malignant phenotype of glioblastoma cells. Int J Oncol 54:1797–1808. https://doi.org/10.3892/ijo.2019.4739

    Article  CAS  PubMed  Google Scholar 

  110. Leyk J, Daly C, Janssen-Bienhold U, Kennedy BN, Richter-Landsberg C (2017) HDAC6 inhibition by Tubastatin A is protective against oxidative stress in a photoreceptor cell line and restores visual function in a zebrafish model of inherited blindness. Cell Death Dis 8:e3028. https://doi.org/10.1038/cddis.2017.415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Jafarpour Azami S, Mohammad Rahimi H, Mirjalali H, Zali MR (2021) Unravelling toxoplasma treatment: conventional drugs toward nanomedicine. World J Microbiol Biotechnol 37:1–9. https://doi.org/10.1007/s11274-021-03000-x

    Article  Google Scholar 

  112. Loeuillet C, Touquet B, Oury B, Eddaikra N, Pons JL, Guichou JF, Labesse G, Sereno D (2018) Synthesis of aminophenylhydroxamate and aminobenzylhydroxamate derivatives and in vitro screening for antiparasitic and histone deacetylase inhibitory activity. Int J Parasitol Drugs Drug Resist 8:59–66. https://doi.org/10.1016/j.ijpddr.2018.01.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Loeuillet C, Touquet B, Guichou JF, Labesse G, Sereno D (2019) A tiny change makes a big difference in the anti-parasitic activities of an HDAC inhibitor. Int J Mol Sci 20. https://doi.org/10.3390/ijms20122973

  114. Striepen B, Yingxin C, Matrajt M, Soldati D, Roos DS (1998) Expression, selection, and organellar targeting of the green fluorescent protein in Toxoplasma gondii. Mol Biochem Parasitol 92:325–338

    Article  CAS  Google Scholar 

  115. Jeffers V, Gao H, Checkley LA, Liu Y, Ferdig MT, Sullivan WJ (2016) Garcinol inhibits GCN5-mediated lysine acetyltransferase activity and prevents replication of the parasite Toxoplasma gondii. Antimicrob Agents Chemother 60:2164–2170. https://doi.org/10.1128/AAC.03059-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Hanquier J, Gimeno T, Jeffers V, Sullivan WJ (2020) Evaluating the GCN5b bromodomain as a novel therapeutic target against the parasite Toxoplasma gondii. Exp Parasitol 211. https://doi.org/10.1016/j.exppara.2020.107868

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  1. Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy

    Paolo Guglielmi & Daniela Secci

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  1. Paolo Guglielmi
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  1. Biotechnology Center-Bioinovar, Biocatalysis, Bioproducts and Bioenergy Unit, Institute of Microbiology Paulo de Góes, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

    Alane Beatriz Vermelho

  2. Polo Scientifico, Laboratorio di Ch, University of Florence, Neurofarba Department, Sesto Fiorentino, Italy

    Claudiu T. Supuran

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Guglielmi, P., Secci, D. (2022). Treatment of Toxoplasmosis: An Insight on Epigenetic Drugs. In: Vermelho, A.B., Supuran, C.T. (eds) Antiprotozoal Drug Development and Delivery. Topics in Medicinal Chemistry, vol 39. Springer, Cham. https://doi.org/10.1007/7355_2021_142

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