Targeting Cysteine Proteases and their Inhibitors to Combat Trypanosomiasis


Cite item

Full Text

Abstract

Background:Trypanosomiasis, caused by protozoan parasites of the Trypanosoma genus, remains a significant health burden in several regions of the world. Cysteine proteases play a crucial role in the pathogenesis of Trypanosoma parasites and have emerged as potential therapeutic targets for the development of novel antiparasitic drugs.

Introduction:This review article aims to provide a comprehensive overview of the role of cysteine proteases in trypanosomiasis and their potential as therapeutic targets. We discuss the biological significance of cysteine proteases in Trypanosoma parasites and their involvement in essential processes, such as host immune evasion, cell invasion, and nutrient acquisition.

Methods:A comprehensive literature search was conducted to identify relevant studies and research articles on the role of cysteine proteases and their inhibitors in trypanosomiasis. The selected studies were critically analyzed to extract key findings and provide a comprehensive overview of the topic.

Results:Cysteine proteases, such as cruzipain, TbCatB and TbCatL, have been identified as promising therapeutic targets due to their essential roles in Trypanosoma pathogenesis. Several small molecule inhibitors and peptidomimetics have been developed to target these proteases and have shown promising activity in preclinical studies.

Conclusion:Targeting cysteine proteases and their inhibitors holds great potential for the development of novel antiparasitic drugs against trypanosomiasis. The identification of potent and selective cysteine protease inhibitors could significantly contribute to the combat against trypanosomiasis and improve the prospects for the treatment of this neglected tropical disease.

About the authors

Aloke Saha

Cell and Developmental Biology Special, Department of Zoology,, University of Kalyani

Email: info@benthamscience.net

Pushpa

Cell and Developmental Biology Special, Department of Zoology,, University of Kalyani

Email: info@benthamscience.net

Susmita Moitra

Cell and Developmental Biology Special, Department of Zoology,, University of Kalyani

Email: info@benthamscience.net

Deblina Basak

Endocrinology Special, Department of Zoology, University of Kalyani

Email: info@benthamscience.net

Sayandeep Brahma

Cell and Developmental Biology Special, Department of Zoology,, University of Kalyani

Email: info@benthamscience.net

Dipu Mondal

Cell and Developmental Biology Special, Department of Zoology, University of Kalyani

Email: info@benthamscience.net

Sabir Molla

Parasitology Laboratory, Department of Zoology,, University of Kalyani

Author for correspondence.
Email: info@benthamscience.net

Asmita Samadder

Cytogenetics and Molecular Biology Lab., Department of Zoology,, University of Kalyani

Author for correspondence.
Email: info@benthamscience.net

Sisir Nandi

, Global Institute of Pharmaceutical Education and Research (Affiliated to Veer Madho Singh Bhandari Uttarakhand Technical University)

Author for correspondence.
Email: info@benthamscience.net

References

  1. Weng, H.B.; Chen, H.X.; Wang, M.W. Innovation in neglected tropical disease drug discovery and development. Infect. Dis. Poverty, 2018, 7(1), 67. doi: 10.1186/s40249-018-0444-1 PMID: 29950174
  2. Kirchhoff, L.V.; Gam, A.A.; Gilliam, F.C. American trypanosomiasis (Chagas’ disease) in central American immigrants. Am. J. Med., 1987, 82(5), 915-920. doi: 10.1016/0002-9343(87)90152-5 PMID: 3107385
  3. Geerts, M.; Van Reet, N.; Leyten, S.; Berghmans, R.; Rock, K.S.; Coetzer, T.H.T.; Eyssen, L.E.A.; Büscher, P. Trypanosoma brucei gambiense-iELISA: A promising new test for the post-elimination monitoring of human African trypanosomiasis. Clin. Infect. Dis., 2021, 73(9), e2477-e2483. doi: 10.1093/cid/ciaa1264 PMID: 32856049
  4. Franco, J.R.; Simarro, P.P.; Diarra, A.; Jannin, J.G. Epidemiology of human African trypanosomiasis. Clin. Epidemiol., 2014, 6, 257-275. PMID: 25125985
  5. Steverding, D. The history of African trypanosomiasis. Parasit. Vectors, 2008, 1(1), 3. doi: 10.1186/1756-3305-1-3 PMID: 18275594
  6. Maxfield, L.; Bermudez, R. Trypanosomiasis. StatPearls; StatPearls Publishing: Treasure Island, FL, 2022.
  7. Gao, J.M.; Qian, Z.Y.; Hide, G.; Lai, D.H.; Lun, Z.R.; Wu, Z.D. Human African trypanosomiasis: The current situation in endemic regions and the risks for non-endemic regions from imported cases. Parasitology, 2020, 147(9), 922-931. doi: 10.1017/S0031182020000645 PMID: 32338232
  8. Aksoy, S.; Buscher, P.; Lehane, M.; Solano, P.; Van Den Abbeele, J. Human African trypanosomiasis control: Achievements and challenges. PLoS Negl. Trop. Dis., 2017, 11(4), e0005454. doi: 10.1371/journal.pntd.0005454 PMID: 28426685
  9. Franco, J.R.; Cecchi, G.; Paone, M.; Diarra, A.; Grout, L.; Kadima Ebeja, A.; Simarro, P.P.; Zhao, W.; Argaw, D. The elimination of human African trypanosomiasis: Achievements in relation to WHO road map targets for 2020. PLoS Negl. Trop. Dis., 2022, 16(1), e0010047. doi: 10.1371/journal.pntd.0010047 PMID: 35041668
  10. Trypanosomiasis, human African. 2023. Available From: https://www.who.int/news-room/fact-sheets/detail/trypanosomiasis-human-african-(sleeping-sickness)
  11. Bern, C.; Kjos, S.; Yabsley, M.J.; Montgomery, S.P. Trypanosoma cruzi and Chagas’ disease in the United States. Clin. Microbiol. Rev., 2011, 24(4), 655-681. doi: 10.1128/CMR.00005-11 PMID: 21976603
  12. Dario, M.A.; Rodrigues, M.S.; Barros, J.H.S.; Xavier, S.C.C.; D’Andrea, P.S.; Roque, A.L.R.; Jansen, A.M. Ecological scenario and Trypanosoma cruzi DTU characterization of a fatal acute Chagas disease case transmitted orally (Espírito Santo state, Brazil). Parasit. Vectors, 2016, 9(1), 477. doi: 10.1186/s13071-016-1754-4 PMID: 27580853
  13. Lidani, K.C.F.; Andrade, F.A.; Bavia, L.; Damasceno, F.S.; Beltrame, M.H.; Messias-Reason, I.J.; Sandri, T.L. Chagas disease: From discovery to a worldwide health problem. Front. Public Health, 2019, 7, 166. doi: 10.3389/fpubh.2019.00166 PMID: 31312626
  14. Bern, C.; Messenger, L.A.; Whitman, J.D.; Maguire, J.H. Chagas disease in the United States: A public health approach. Clin. Microbiol. Rev., 2019, 33(1), e00023-e19. doi: 10.1128/CMR.00023-19 PMID: 31776135
  15. Schmunis, G.A.; Yadon, Z.E. Chagas disease: A Latin American health problem becoming a world health problem. Acta Trop., 2010, 115(1-2), 14-21. doi: 10.1016/j.actatropica.2009.11.003 PMID: 19932071
  16. Solomon Ngutor, K.; Idris, L.A.; Oluseyi Oluyinka, O. Silent human Trypanosoma brucei gambiense infections around the old gboko sleeping sickness focus in Nigeria. J. Parasitol. Res., 2016, 2016, 1-5. doi: 10.1155/2016/2656121 PMID: 26941995
  17. Kasozi, K.I.; Zirintunda, G.; Ssempijja, F.; Buyinza, B.; Alzahrani, K.J.; Matama, K.; Nakimbugwe, H.N.; Alkazmi, L.; Onanyang, D.; Bogere, P.; Ochieng, J.J.; Islam, S.; Matovu, W.; Nalumenya, D.P.; Batiha, G.E.S.; Osuwat, L.O.; Abdelhamid, M.; Shen, T.; Omadang, L.; Welburn, S.C. Epidemiology of trypanosomiasis in wildlife-implications for humans at the wildlife interface in Africa. Front. Vet. Sci., 2021, 8, 621699. doi: 10.3389/fvets.2021.621699 PMID: 34222391
  18. Meisner, J.; Kato, A.; Lemerani, M.M.; Mwamba Miaka, E.; Ismail Taban, A.; Wakefield, J.; Rowhani-Rahbar, A.; Pigott, D.M.; Mayer, J.D.; Rabinowitz, P.M. The effect of livestock density on Trypanosoma brucei gambiense and T. b. rhodesiense: A causal inference-based approach. PLoS Negl. Trop. Dis., 2022, 16(8), e0010155. doi: 10.1371/journal.pntd.0010155 PMID: 36037205
  19. Greenwood, B.M.; Whittle, H.C. The pathogenesis of sleeping sickness. Trans. R. Soc. Trop. Med. Hyg., 1980, 74(6), 716-725. doi: 10.1016/0035-9203(80)90184-4 PMID: 7010694
  20. Schuster, S.; Lisack, J.; Subota, I.; Zimmermann, H.; Reuter, C.; Mueller, T.; Morriswood, B.; Engstler, M. Unexpected plasticity in the life cycle of Trypanosoma brucei. eLife, 2021, 10, e66028. doi: 10.7554/eLife.66028 PMID: 34355698
  21. Lindner, A.K.; Priotto, G. The unknown risk of vertical transmission in sleeping sickness-a literature review. PLoS Negl. Trop. Dis., 2010, 4(12), e783. doi: 10.1371/journal.pntd.0000783 PMID: 21200416
  22. Laperchia, C.; Palomba, M.; Seke Etet, P.F.; Rodgers, J.; Bradley, B.; Montague, P.; Grassi-Zucconi, G.; Kennedy, P.G.E.; Bentivoglio, M. Trypanosoma brucei invasion and T-cell infiltration of the brain parenchyma in experimental sleeping sickness: Timing and correlation with functional changes. PLoS Negl. Trop. Dis., 2016, 10(12), e0005242. doi: 10.1371/journal.pntd.0005242 PMID: 28002454
  23. Rijo-Ferreira, F.; Takahashi, J.S. Sleeping sickness: A tale of two clocks. Front. Cell. Infect. Microbiol., 2020, 10, 525097. doi: 10.3389/fcimb.2020.525097 PMID: 33134186
  24. Lundkvist, G.B.; Kristensson, K.; Bentivoglio, M. Why trypanosomes cause sleeping sickness. Physiology, 2004, 19(4), 198-206. doi: 10.1152/physiol.00006.2004 PMID: 15304634
  25. Barrett, M.P.; Croft, S.L. Management of trypanosomiasis and leishmaniasis. Br. Med. Bull., 2012, 104(1), 175-196. doi: 10.1093/bmb/lds031 PMID: 23137768
  26. Palmer, J.J. Sensing sleeping sickness: Local symptom-making in South Sudan. Med. Anthropol., 2020, 39(6), 457-473. doi: 10.1080/01459740.2019.1689976 PMID: 31852244
  27. Boatin, B.A.; Wyatt, G.B.; Wurapa, F.K.; Bulsara, M.K. Use of symptoms and signs for diagnosis of Trypanosoma brucei rhodesiense trypanosomiasis by rural health personnel. Bull. World Health Organ., 1986, 64(3), 389-395. PMID: 3490318
  28. Kennedy, P.G.E. Clinical features, diagnosis, and treatment of human African trypanosomiasis (sleeping sickness). Lancet Neurol., 2013, 12(2), 186-194. doi: 10.1016/S1474-4422(12)70296-X PMID: 23260189
  29. Caffrey, C.; Scory, S.; Steverding, D. Cysteine proteinases of trypanosome parasites: Novel targets for chemotherapy. Curr. Drug Targets, 2000, 1(2), 155-162. doi: 10.2174/1389450003349290 PMID: 11465068
  30. Vago, A.R.; Silva, D.M.; Adad, S.J.; Correa-Oliveira, R.; Reis, D.Á. Chronic Chagas disease: Presence of parasite DNA in the oesophagus of patients without megaoesophagus. Trans. R. Soc. Trop. Med. Hyg., 2003, 97(3), 308-309. doi: 10.1016/S0035-9203(03)90155-6 PMID: 15228249
  31. de Meis, J.; Barreto de Albuquerque, J.; Silva dos Santos, D.; Farias-de-Oliveira, D.A.; Berbert, L.R.; Cotta-de-Almeida, V.; Savino, W. Trypanosoma cruzi entrance through systemic or mucosal infection sites differentially modulates regional immune response following acute infection in mice. Front. Immunol., 2013, 4, 216. doi: 10.3389/fimmu.2013.00216 PMID: 23898334
  32. Tarleton, R.L. Trypanosoma cruzi and Chagas disease: Cause and effect. American Trypanosomiasis; Tyler, K.M; Miles, M.A., Ed.; Springer US: Boston, MA, 2003, Vol. 7, pp. 107-115. doi: 10.1007/978-1-4419-9206-2_10
  33. Siklos, M.; BenAissa, M.; Thatcher, G.R.J. Cysteine proteases as therapeutic targets: Does selectivity matter? A systematic review of calpain and cathepsin inhibitors. Acta Pharm. Sin. B, 2015, 5(6), 506-519. doi: 10.1016/j.apsb.2015.08.001 PMID: 26713267
  34. Beatriz Vermelho, A. Trypanosoma cruzi peptidases: An overview. Open Parasitol. J., 2010, 4(1), 120-131. doi: 10.2174/1874421401004010120
  35. Bossard, G.; Cuny, G.; Geiger, A. Secreted proteases of Trypanosoma brucei gambiense: Possible targets for sleeping sickness control? Biofactors, 2013, 39(4), 407-414. doi: 10.1002/biof.1100 PMID: 23553721
  36. Troeberg, L.; Pike, R.N.; Morty, R.E.; Berry, R.K.; Coetzer, T.H.T.; Lonsdale-Eccles, J.D. Proteases from Trypanosoma brucei brucei. Purification, characterisation and interactions with host regulatory molecules. Eur. J. Biochem., 1996, 238(3), 728-736. doi: 10.1111/j.1432-1033.1996.0728w.x PMID: 8706674
  37. Verma, S.; Dixit, R.; Pandey, K.C. Cysteine proteases: Modes of activation and future prospects as pharmacological targets. Front. Pharmacol., 2016, 7, 107. doi: 10.3389/fphar.2016.00107 PMID: 27199750
  38. Coulombe, R.; Grochulski, P.; Sivaraman, J.; Ménard, R.; Mort, J.S.; Cygler, M. Structure of human procathepsin L reveals the molecular basis of inhibition by the prosegment. EMBO J., 1996, 15(20), 5492-5503. doi: 10.1002/j.1460-2075.1996.tb00934.x PMID: 8896443
  39. Yan, H.B.; Lou, Z.Z.; Li, L.; Brindley, P.J.; Zheng, Y.; Luo, X.; Hou, J.; Guo, A.; Jia, W.Z.; Cai, X. Genome-wide analysis of regulatory proteases sequences identified through bioinformatics data mining in Taenia solium. BMC Genomics, 2014, 15(1), 428. doi: 10.1186/1471-2164-15-428 PMID: 24899069
  40. Puente, X.S.; Sánchez, L.M.; Overall, C.M.; López-Otín, C. Human and mouse proteases: A comparative genomic approach. Nat. Rev. Genet., 2003, 4(7), 544-558. doi: 10.1038/nrg1111 PMID: 12838346
  41. Santos, C.C.; Sant’anna, C.; Terres, A.; Cunha-e-Silva, N.L.; Scharfstein, J. de A Lima, A.P. Chagasin, the endogenous cysteine-protease inhibitor of Trypanosoma cruzi, modulates parasite differentiation and invasion of mammalian cells. J. Cell Sci., 2005, 118(Pt 5), 901-915. doi: 10.1242/jcs.01677 PMID: 15713748
  42. Erez, E.; Fass, D.; Bibi, E. How intramembrane proteases bury hydrolytic reactions in the membrane. Nature, 2009, 459(7245), 371-378. doi: 10.1038/nature08146 PMID: 19458713
  43. Schechter, I.; Berger, A. On the size of the active site in proteases. I. Papain. Biochem. Biophys. Res. Commun., 1967, 27(2), 157-162. doi: 10.1016/S0006-291X(67)80055-X PMID: 6035483
  44. Rosenthal, P.; Sijwali, P.; Singh, A.; Shenai, B. Cysteine proteases of malaria parasites: Targets for chemotherapy. Curr. Pharm. Des., 2002, 8(18), 1659-1672. doi: 10.2174/1381612023394197 PMID: 12132997
  45. Pandey, K.C.; Dixit, R. Structure-function of falcipains: Malarial cysteine proteases. J. Trop. Med., 2012, 2012, 1-11. doi: 10.1155/2012/345195 PMID: 22529862
  46. Pišlar, A. Mitrović A.; Sabotič J.; Pečar Fonović U.; Perišić Nanut, M.; Jakoš, T.; Senjor, E.; Kos, J. The role of cysteine peptidases in coronavirus cell entry and replication: The therapeutic potential of cathepsin inhibitors. PLoS Pathog., 2020, 16(11), e1009013. doi: 10.1371/journal.ppat.1009013 PMID: 33137165
  47. Osipiuk, J.; Azizi, S.A.; Dvorkin, S.; Endres, M.; Jedrzejczak, R.; Jones, K.A.; Kang, S.; Kathayat, R.S.; Kim, Y.; Lisnyak, V.G.; Maki, S.L.; Nicolaescu, V.; Taylor, C.A.; Tesar, C.; Zhang, Y.A.; Zhou, Z.; Randall, G.; Michalska, K.; Snyder, S.A.; Dickinson, B.C.; Joachimiak, A. Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors. Nat. Commun., 2021, 12(1), 743. doi: 10.1038/s41467-021-21060-3 PMID: 33531496
  48. Cho, C.C.; Li, S.G.; Lalonde, T.J.; Yang, K.S.; Yu, G.; Qiao, Y.; Xu, S.; Ray Liu, W. Drug repurposing for the SARS-CoV-2 papain-like protease. ChemMedChem, 2022, 17(1), e202100455. doi: 10.1002/cmdc.202100455 PMID: 34423563
  49. Sajid, M.; McKerrow, J.H. Cysteine proteases of parasitic organisms. Mol. Biochem. Parasitol., 2002, 120(1), 1-21. doi: 10.1016/S0166-6851(01)00438-8 PMID: 11849701
  50. Steverding, D.; Sexton, D.W.; Wang, X.; Gehrke, S.S.; Wagner, G.K.; Caffrey, C.R. Trypanosoma brucei: Chemical evidence that cathepsin L is essential for survival and a relevant drug target. Int. J. Parasitol., 2012, 42(5), 481-488. doi: 10.1016/j.ijpara.2012.03.009 PMID: 22549023
  51. Rosas-Jimenez, J.G.; Garcia-Revilla, M.A.; Madariaga-Mazon, A.; Martinez-Mayorga, K. Predictive global models of Cruzain inhibitors with large chemical coverage. ACS Omega, 2021, 6(10), 6722-6735. doi: 10.1021/acsomega.0c05645 PMID: 33748586
  52. Barbosa da Silva, E.; Dall, E.; Briza, P.; Brandstetter, H.; Ferreira, R.S. Cruzain structures: Apocruzain and cruzain bound to S-methyl thiomethanesulfonate and implications for drug design. Acta Crystallogr. F Struct. Biol. Commun., 2019, 75(6), 419-427. doi: 10.1107/S2053230X19006320 PMID: 31204688
  53. Turk, V.; Stoka, V.; Vasiljeva, O.; Renko, M.; Sun, T.; Turk, B.; Turk, D. Cysteine cathepsins: From structure, function and regulation to new frontiers. Biochim. Biophys. Acta. Proteins Proteomics, 2012, 1824(1), 68-88. doi: 10.1016/j.bbapap.2011.10.002 PMID: 22024571
  54. Kerr, I.D.; Wu, P.; Marion-Tsukamaki, R.; Mackey, Z.B.; Brinen, L.S. Crystal Structures of TbCatB and rhodesain, potential chemotherapeutic targets and major cysteine proteases of Trypanosoma brucei. PLoS Negl. Trop. Dis., 2010, 4(6), e701. doi: 10.1371/journal.pntd.0000701 PMID: 20544024
  55. Martinez-Mayorga, K.; Byler, K.G.; Ramirez-Hernandez, A.I.; Terrazas-Alvares, D.E. Cruzain inhibitors: Efforts made, current leads and a structural outlook of new hits. Drug Discov. Today, 2015, 20(7), 890-898. doi: 10.1016/j.drudis.2015.02.004 PMID: 25697479
  56. Nicoll-Griffith, D.A. Use of cysteine-reactive small molecules in drug discovery for trypanosomal disease. Expert Opin. Drug Discov., 2012, 7(4), 353-366. doi: 10.1517/17460441.2012.668520 PMID: 22458506
  57. Grab, D.J.; Garcia-Garcia, J.C.; Nikolskaia, O.V.; Kim, Y.V.; Brown, A.; Pardo, C.A.; Zhang, Y.; Becker, K.G.; Wilson, B.A. de A Lima, A.P.; Scharfstein, J.; Dumler, J.S. Protease activated receptor signaling is required for African trypanosome traversal of human brain microvascular endothelial cells. PLoS Negl. Trop. Dis., 2009, 3(7), e479. doi: 10.1371/journal.pntd.0000479 PMID: 19621073
  58. Johé, P.; Jaenicke, E.; Neuweiler, H.; Schirmeister, T.; Kersten, C.; Hellmich, U.A. Structure, interdomain dynamics, and pH-dependent autoactivation of pro-rhodesain, the main lysosomal cysteine protease from African trypanosomes. J. Biol. Chem., 2021, 296, 100565. doi: 10.1016/j.jbc.2021.100565 PMID: 33745969
  59. Kamphuis, I.G.; Kalk, K.H.; Swarte, M.B.A.; Drenth, J. Structure of papain refined at 1.65 Å resolution. J. Mol. Biol., 1984, 179(2), 233-256. doi: 10.1016/0022-2836(84)90467-4 PMID: 6502713
  60. Roy, S.; Choudhury, D.; Aich, P.; Dattagupta, J.K.; Biswas, S. The structure of a thermostable mutant of pro-papain reveals its activation mechanism. Acta Crystallogr. D Biol. Crystallogr., 2012, 68(12), 1591-1603. doi: 10.1107/S0907444912038607 PMID: 23151624
  61. Rawlings, N.D.; Barrett, A.J.; Thomas, P.D.; Huang, X.; Bateman, A.; Finn, R.D. The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database. Nucleic Acids Res., 2018, 46(D1), D624-D632. doi: 10.1093/nar/gkx1134 PMID: 29145643
  62. Vernet, T.; Berti, P.J.; de Montigny, C.; Musil, R.; Tessier, D.C.; Ménard, R.; Magny, M.C.; Storer, A.C.; Thomas, D.Y. Processing of the papain precursor. The ionization state of a conserved amino acid motif within the Pro region participates in the regulation of intramolecular processing. J. Biol. Chem., 1995, 270(18), 10838-10846. doi: 10.1074/jbc.270.18.10838 PMID: 7738022
  63. Troeberg, L.; Morty, R.E.; Pike, R.N.; Lonsdale-Eccles, J.D.; Palmer, J.T.; McKerrow, J.H.; Coetzer, T.H.T. Cysteine proteinase inhibitors kill cultured bloodstream forms of Trypanosoma brucei brucei. Exp. Parasitol., 1999, 91(4), 349-355. doi: 10.1006/expr.1998.4386 PMID: 10092479
  64. Scharfstein, J.; Schmitz, V.; Morandi, V.; Capella, M.M.A.; Lima, A.P.C.A.; Morrot, A.; Juliano, L.; Müller-Esterl, W. Host cell invasion by Trypanosoma cruzi is potentiated by activation of bradykinin B(2) receptors. J. Exp. Med., 2000, 192(9), 1289-1300. doi: 10.1084/jem.192.9.1289 PMID: 11067878
  65. Mackey, Z.B.; O’Brien, T.C.; Greenbaum, D.C.; Blank, R.B.; McKerrow, J.H. A cathepsin B-like protease is required for host protein degradation in Trypanosoma brucei. J. Biol. Chem., 2004, 279(46), 48426-48433. doi: 10.1074/jbc.M402470200 PMID: 15326171
  66. Girard, M.; Giraud, S.; Courtioux, B.; Jauberteau-Marchan, M.O.; Bouteille, B. Endothelial cell activation in the presence of African trypanosomes. Mol. Biochem. Parasitol., 2005, 139(1), 41-49. doi: 10.1016/j.molbiopara.2004.09.008 PMID: 15610818
  67. Aparicio, I.M.; Scharfstein, J.; Lima, A.P.C.A. A new cruzipain-mediated pathway of human cell invasion by Trypanosoma cruzi requires trypomastigote membranes. Infect. Immun., 2004, 72(10), 5892-5902. doi: 10.1128/IAI.72.10.5892-5902.2004 PMID: 15385491
  68. Caffrey, C.R.; Hansell, E.; Lucas, K.D.; Brinen, L.S.; Alvarez Hernandez, A.; Cheng, J.; Gwaltney, S.L., II; Roush, W.R.; Stierhof, Y.D.; Bogyo, M.; Steverding, D.; McKerrow, J.H. Active site mapping, biochemical properties and subcellular localization of rhodesain, the major cysteine protease of Trypanosoma brucei rhodesiense. Mol. Biochem. Parasitol., 2001, 118(1), 61-73. doi: 10.1016/S0166-6851(01)00368-1 PMID: 11704274
  69. Grab, D.J.; Nikolskaia, O.; Kim, Y.V.; Lonsdale-Eccles, J.D.; Ito, S.; Hara, T.; Fukuma, T.; Nyarko, E.; Kim, K.J.; Stins, M.F.; Delannoy, M.J.; Rodgers, J.; Kim, K.S. African trypanosome interactions with an in vitro model of the human blood-brain barrier. J. Parasitol., 2004, 90(5), 970-979. doi: 10.1645/GE-287R PMID: 15562595
  70. Meirelles, M.N.L.; Juliano, L.; Carmona, E.; Silva, S.G.; Costa, E.M.; Murta, A.C.M.; Scharfstein, J. Inhibitors of the major cysteinyl proteinase (GP57/51) impair host cell invasion and arrest the intracellular development of Trypanosoma cruzi in vitro. Mol. Biochem. Parasitol., 1992, 52(2), 175-184. doi: 10.1016/0166-6851(92)90050-T PMID: 1620157
  71. Bonaldo, M.C.; d’Escoffier, L.N.; Salles, J.M.; Goldenberg, S. Characterization and expression of proteases during Trypanosoma cruzi metacyclogenesis. Exp. Parasitol., 1991, 73(1), 44-51. doi: 10.1016/0014-4894(91)90006-I PMID: 2055300
  72. Gazzinelli, R.T.; Leme, V.M.; Cancado, J.R.; Gazzinelli, G.; Scharfstein, J. Identification and partial characterization of Trypanosoma cruzi antigens recognized by T cells and immune sera from patients with Chagas’ disease. Infect. Immun., 1990, 58(5), 1437-1444. doi: 10.1128/iai.58.5.1437-1444.1990 PMID: 2108932
  73. Carbonetto, C.H.; Malchiodi, E.L.; Chiaramonte, M.; De Isola, D.; Fossati, C.A.; Margni, R.A. Isolation of a Trypanosoma cruzi antigen by affinity chromatography with a monoclonal antibody. Preliminary evaluation of its possible applications in serological tests. Clin. Exp. Immunol., 2008, 82(1), 93-96. doi: 10.1111/j.1365-2249.1990.tb05409.x PMID: 2119921
  74. Duschak, V.G.; Riarte, A.; Segura, E.L.; Laucella, S.A. Humoral immune response to cruzipain and cardiac dysfunction in chronic Chagas disease. Immunol. Lett., 2001, 78(3), 135-142. doi: 10.1016/S0165-2478(01)00255-3 PMID: 11578687
  75. Martínez, J.; Campetella, O.; Frasch, A.C.C.; Cazzulo, J.J. The reactivity of sera from chagasic patients against different fragments of cruzipain, the major cysteine proteinase from Trypanosoma cruzi, suggests the presence of defined antigenic and catalytic domains. Immunol. Lett., 1993, 35(2), 191-196. doi: 10.1016/0165-2478(93)90090-O PMID: 7685319
  76. Murta, A.C.M.; Persechini, P.M.; Padron, T.S.; de Souza, W.; Guimarães, J.A.; Scharfstein, J. Structural and functional identification of GP57/51 antigen of Trypanosoma cruzi as a cysteine proteinase. Mol. Biochem. Parasitol., 1990, 43(1), 27-38. doi: 10.1016/0166-6851(90)90127-8 PMID: 1705310
  77. Lima, A.P.C.; Tessier, D.C.; Thomas, D.Y.; Scharfstein, J.; Storer, A.C.; Vernet, T. Identification of new cysteine protease gene isoforms in Trypanosoma cruzi. Mol. Biochem. Parasitol., 1994, 67(2), 333-338. doi: 10.1016/0166-6851(94)00144-8 PMID: 7870137
  78. Eakin, A.E.; Mills, A.A.; Harth, G.; McKerrow, J.H.; Craik, C.S. The sequence, organization, and expression of the major cysteine protease (cruzain) from Trypanosoma cruzi. J. Biol. Chem., 1992, 267(11), 7411-7420. 7411. 7420 doi: 10.1016/S0021-9258(18)42533-1 PMID: 1559982
  79. Gillmor, S.A.; Craik, C.S.; Fletterick, R.J. Structural determinants of specificity in the cysteine protease cruzain. Protein Sci., 1997, 6(8), 1603-1611. doi: 10.1002/pro.5560060801 PMID: 9260273
  80. Santos, V.C.; Oliveira, A.E.R.; Campos, A.C.B.; Reis-Cunha, J.L.; Bartholomeu, D.C.; Teixeira, S.M.R.; Lima, A.P.C.A.; Ferreira, R.S. The gene repertoire of the main cysteine protease of Trypanosoma cruzi, cruzipain, reveals four sub-types with distinct active sites. Sci. Rep., 2021, 11(1), 18231. doi: 10.1038/s41598-021-97490-2 PMID: 34521898
  81. Judice, W.A.S.; Cezari, M.H.S.; Lima, A.P.C.A.; Scharfstein, J.; Chagas, J.R.; Tersariol, I.L.S.; Juliano, M.A.; Juliano, L. Comparison of the specificity, stability and individual rate constants with respective activation parameters for the peptidase activity of cruzipain and its recombinant form, cruzain, from Trypanosoma cruzi. Eur. J. Biochem., 2001, 268(24), 6578-6586. doi: 10.1046/j.0014-2956.2001.02612.x PMID: 11737212
  82. McGrath, M.E.; Eakin, A.E.; Engel, J.C.; McKerrow, J.H.; Craik, C.S.; Fletterick, R.J. The crystal structure of cruzain: A therapeutic target for Chagas’ disease. J. Mol. Biol., 1995, 247(2), 251-259. doi: 10.1006/jmbi.1994.0137 PMID: 7707373
  83. Barbosa Da Silva, E.; Sharma, V.; Hernandez-Alvarez, L.; Tang, A.H.; Stoye, A.; O’Donoghue, A.J.; Gerwick, W.H.; Payne, R.J.; McKerrow, J.H.; Podust, L.M. Intramolecular interactions enhance the potency of gallinamide a analogues against Trypanosoma cruzi. J. Med. Chem., 2022, 65(5), 4255-4269. doi: 10.1021/acs.jmedchem.1c02063 PMID: 35188371
  84. Lima, A.P.C.A.; dos Reis, F.C.G.; Serveau, C.; Lalmanach, G.; Juliano, L.; Ménard, R.; Vernet, T.; Thomas, D.Y.; Storer, A.C.; Scharfstein, J. Cysteine protease isoforms from Trypanosoma cruzi, cruzipain 2 and cruzain, present different substrate preference and susceptibility to inhibitors. Mol. Biochem. Parasitol., 2001, 114(1), 41-52. doi: 10.1016/S0166-6851(01)00236-5 PMID: 11356512
  85. Lima, A.P.C.A.; Almeida, P.C.; Tersariol, I.L.S.; Schmitz, V.; Schmaier, A.H.; Juliano, L.; Hirata, I.Y.; Müller-Esterl, W.; Chagas, J.R.; Scharfstein, J. Heparan sulfate modulates kinin release by Trypanosoma cruzi through the activity of cruzipain. J. Biol. Chem., 2002, 277(8), 5875-5881. doi: 10.1074/jbc.M108518200 PMID: 11726662
  86. Talavera-López, C.; Messenger, L.A.; Lewis, M.D.; Yeo, M.; Reis-Cunha, J.L.; Matos, G.M.; Bartholomeu, D.C.; Calzada, J.E.; Saldaña, A.; Ramírez, J.D.; Guhl, F.; Ocaña-Mayorga, S.; Costales, J.A.; Gorchakov, R.; Jones, K.; Nolan, M.S.; Teixeira, S.M.R.; Carrasco, H.J.; Bottazzi, M.E.; Hotez, P.J.; Murray, K.O.; Grijalva, M.J.; Burleigh, B.; Grisard, E.C.; Miles, M.A.; Andersson, B. Repeat-driven generation of antigenic diversity in a major human pathogen, Trypanosoma cruzi. Front. Cell. Infect. Microbiol., 2021, 11, 614665. doi: 10.3389/fcimb.2021.614665 PMID: 33747978
  87. Weatherly, D.B.; Peng, D.; Tarleton, R.L. Recombination-driven generation of the largest pathogen repository of antigen variants in the protozoan Trypanosoma cruzi. BMC Genomics, 2016, 17(1), 729. doi: 10.1186/s12864-016-3037-z PMID: 27619017
  88. Campetella, O.; Henriksson, J.; Åslund, U.; Frasch, A.C.C.; Pettersson, U.; Cazzulo, J.J. The major cysteine proteinase (cruzipain) from Trypanosoma cruzi is encoded by multiple polymorphic tandemly organized genes located on different chromosomes. Mol. Biochem. Parasitol., 1992, 50(2), 225-234. doi: 10.1016/0166-6851(92)90219-A PMID: 1311053
  89. Denise, H.; Barrett, M.P. Uptake and mode of action of drugs used against sleeping sickness. Biochem. Pharmacol., 2001, 61(1), 1-5. doi: 10.1016/S0006-2952(00)00477-9 PMID: 11137702
  90. Coura, J.R.; Abreu, L.L.; Willcox, H.P.F.; Petana, W. Estudo comparativo controlado com emprego de benznidazole, nifurtimox e placebo, na forma crônica da doença de Chagas, em uma área de campo com transmissão interrompida. I. Avaliação preliminar. Rev. Soc. Bras. Med. Trop., 1997, 30(2), 139-144. doi: 10.1590/S0037-86821997000200009 PMID: 9148337
  91. Pollastri, M.P. Fexinidazole: A new drug for african sleeping sickness on the horizon. Trends Parasitol., 2018, 34(3), 178-179. doi: 10.1016/j.pt.2017.12.002 PMID: 29275007
  92. Bahia, M.T.; Andrade, I.M.; Martins, T.A.F.; Nascimento, Á.F.S.; Diniz, L.F.; Caldas, I.S.; Talvani, A.; Trunz, B.B.; Torreele, E.; Ribeiro, I. Fexinidazole: A potential new drug candidate for Chagas disease. PLoS Negl. Trop. Dis., 2012, 6(11), e1870. doi: 10.1371/journal.pntd.0001870 PMID: 23133682
  93. Wéry, M. Drug used in the treatment of sleeping sickness (human African trypanosomiasis: HAT). Int. J. Antimicrob. Agents, 1994, 4(3), 227-238. doi: 10.1016/0924-8579(94)90012-4 PMID: 18611614
  94. Voogd, T.E.; Vansterkenburg, E.L.; Wilting, J.; Janssen, L.H. Recent research on the biological activity of suramin. Pharmacol. Rev., 1993, 45(2), 177-203. PMID: 8396782
  95. Steverding, D. The development of drugs for treatment of sleeping sickness: A historical review. Parasit. Vectors, 2010, 3(1), 15. doi: 10.1186/1756-3305-3-15 PMID: 20219092
  96. Fairlamb, A.H. Chemotherapy of human African trypanosomiasis: Current and future prospects. Trends Parasitol., 2003, 19(11), 488-494. doi: 10.1016/j.pt.2003.09.002 PMID: 14580959
  97. Barrett, S.V.; Barrett, M.P. Anti-sleeping sickness drugs and cancer chemotherapy. Parasitol. Today, 2000, 16(1), 7-9. doi: 10.1016/S0169-4758(99)01560-4 PMID: 10637579
  98. Barrett, M.P.; Boykin, D.W.; Brun, R.; Tidwell, R.R. Human African trypanosomiasis: Pharmacological reengagement with a neglected disease. Br. J. Pharmacol., 2007, 152(8), 1155-1171. doi: 10.1038/sj.bjp.0707354 PMID: 17618313
  99. Paine, M.F.; Wang, M.Z.; Generaux, C.N.; Boykin, D.W.; Wilson, W.D.; De Koning, H.P.; Olson, C.A.; Pohlig, G.; Burri, C.; Brun, R.; Murilla, G.A.; Thuita, J.K.; Barrett, M.P.; Tidwell, R.R. Diamidines for human African trypanosomiasis. Curr. Opin. Investig. Drugs, 2010, 11(8), 876-883. PMID: 20721830
  100. Shapiro, T.A.; Englund, P.T. Selective cleavage of kinetoplast DNA minicircles promoted by anti trypanosomal drugs. Proc. Natl. Acad. Sci. USA, 1990, 87(3), 950-954. doi: 10.1073/pnas.87.3.950 PMID: 2153980
  101. Bosch, F.; Rosich, L. The contributions of Paul Ehrlich to pharmacology: A tribute on the occasion of the centenary of his Nobel Prize. Pharmacology, 2008, 82(3), 171-179. doi: 10.1159/000149583 PMID: 18679046
  102. Carter, N.S.; Fairlamb, A.H. Arsenical-resistant trypanosomes lack an unusual adenosine transporter. Nature, 1993, 361(6408), 173-176. doi: 10.1038/361173a0 PMID: 8421523
  103. Barrett, M.P.; Fairlamb, A.H. The biochemical basis of arsenical-diamidine crossresistance in African trypanosomes. Parasitol. Today, 1999, 15(4), 136-140. doi: 10.1016/S0169-4758(99)01414-3 PMID: 10322334
  104. Schaftingen, E.; Opperdoes, F.R.; Hers, H.G. Effects of various metabolic conditions and of the trivalent arsenical melarsen oxide on the intracellular levels of fructose 2,6-bisphosphate and of glycolytic intermediates in Trypanosoma brucei. Eur. J. Biochem., 1987, 166(3), 653-661. doi: 10.1111/j.1432-1033.1987.tb13563.x PMID: 3038548
  105. Brun, R.; Don, R.; Jacobs, R.T.; Wang, M.Z.; Barrett, M.P. Development of novel drugs for human African trypanosomiasis. Future Microbiol., 2011, 6(6), 677-691. doi: 10.2217/fmb.11.44 PMID: 21707314
  106. Bacchi, C.J.; Nathan, H.C.; Hutner, S.H.; McCann, P.P.; Sjoerdsma, A. Polyamine metabolism: A potential therapeutic target in trypanosomes. Science, 1980, 210(4467), 332-334. doi: 10.1126/science.6775372 PMID: 6775372
  107. Docampo, R.; Moreno, S.N.J.; Stoppani, A.O.M.; Leon, W.; Cruz, F.S.; Villalta, F.; Muniz, R.F.A. Mechanism of nifurtimox toxicity in different forms of Trypanosoma cruzi. Biochem. Pharmacol., 1981, 30(14), 1947-1951. doi: 10.1016/0006-2952(81)90204-5 PMID: 7023488
  108. Tsuhako, M.H.; Alves, M.J.M.; Colli, W.; Filardi, L.S.; Brener, Z.; Augusto, O. Comparative studies of nifurtimox uptake and metabolism by drug-resistant and susceptible strains of Trypanosoma cruzi. Comp. Biochem. Physiol. C Comp. Pharmacol., 1991, 99(3), 317-321. doi: 10.1016/0742-8413(91)90248-R PMID: 1685402
  109. Pépin, J.; Milord, F.; Meurice, F.; Ethier, L.; Loko, L.; Mpia, B. High-dose nifurtimox for arseno-resistant Trypanosoma brucei gambiense sleeping sickness: An open trial in central Zaire. Trans. R. Soc. Trop. Med. Hyg., 1992, 86(3), 254-256. doi: 10.1016/0035-9203(92)90298-Q PMID: 1412646
  110. Dias, J.C.P.; Coura, J.R.; Yasuda, M.A.S. The present situation, challenges, and perspectives regarding the production and utilization of effective drugs against human Chagas disease. Rev. Soc. Bras. Med. Trop., 2014, 47(1), 123-125. doi: 10.1590/0037-8682-0248-2013 PMID: 24603750
  111. Pinazo, M.J.; Guerrero, L.; Posada, E.; Rodríguez, E.; Soy, D.; Gascon, J. Benznidazole-related adverse drug reactions and their relationship to serum drug concentrations in patients with chronic chagas disease. Antimicrob. Agents Chemother., 2013, 57(1), 390-395. doi: 10.1128/AAC.01401-12 PMID: 23114763
  112. Kaiser, M.; Bray, M.A.; Cal, M.; Bourdin Trunz, B.; Torreele, E.; Brun, R. Anti trypanosomal activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of sleeping sickness. Antimicrob. Agents Chemother., 2011, 55(12), 5602-5608. doi: 10.1128/AAC.00246-11 PMID: 21911566
  113. Torreele, E.; Bourdin Trunz, B.; Tweats, D.; Kaiser, M.; Brun, R.; Mazué, G.; Bray, M.A.; Pécoul, B. Fexinidazole--a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness. PLoS Negl. Trop. Dis., 2010, 4(12), e923. doi: 10.1371/journal.pntd.0000923 PMID: 21200426
  114. Ding, D.; Zhao, Y.; Meng, Q.; Xie, D.; Nare, B.; Chen, D.; Bacchi, C.J.; Yarlett, N.; Zhang, Y.K.; Hernandez, V.; Xia, Y.; Freund, Y.; Abdulla, M.; Ang, K.H.; Ratnam, J.; McKerrow, J.H.; Jacobs, R.T.; Zhou, H.; Plattner, J.J. Discovery of novel benzoxaborole-based potent anti trypanosomal agents. ACS Med. Chem. Lett., 2010, 1(4), 165-169. doi: 10.1021/ml100013s PMID: 24900190
  115. Jones, D.C.; Foth, B.J.; Urbaniak, M.D.; Patterson, S.; Ong, H.B.; Berriman, M.; Fairlamb, A.H. Genomic and proteomic studies on the mode of action of oxaboroles against the African trypanosome. PLoS Negl. Trop. Dis., 2015, 9(12), e0004299. doi: 10.1371/journal.pntd.0004299 PMID: 26684831
  116. Unciti-Broceta, J.D.; Maceira, J.; Morales, S.; García-Pérez, A.; Muñóz-Torres, M.E.; Garcia-Salcedo, J.A. Nicotinamide inhibits the lysosomal cathepsin b-like protease and kills African trypanosomes. J. Biol. Chem., 2013, 288(15), 10548-10557. doi: 10.1074/jbc.M112.449207 PMID: 23443665
  117. Steverding, D.; Rushworth, S.A.; Florea, B.I.; Overkleeft, H.S. Trypanosoma brucei: Inhibition of cathepsin L is sufficient to kill bloodstream forms. Mol. Biochem. Parasitol., 2020, 235, 111246. doi: 10.1016/j.molbiopara.2019.111246 PMID: 31743688
  118. Chen, Y.T.; Lira, R.; Hansell, E.; McKerrow, J.H.; Roush, W.R. Synthesis of macrocyclic trypanosomal cysteine protease inhibitors. Bioorg. Med. Chem. Lett., 2008, 18(22), 5860-5863. doi: 10.1016/j.bmcl.2008.06.012 PMID: 18585034
  119. Ferreira, L.G.; Andricopulo, A.D. Targeting cysteine proteases in Trypanosomatid disease drug discovery. Pharmacol. Ther., 2017, 180, 49-61. doi: 10.1016/j.pharmthera.2017.06.004 PMID: 28579388
  120. Du, X.; Hansell, E.; Engel, J.C.; Caffrey, C.R.; Cohen, F.E.; McKerrow, J.H. Aryl ureas represent a new class of anti-trypanosomal agents. Chem. Biol., 2000, 7(9), 733-742. doi: 10.1016/S1074-5521(00)00018-1 PMID: 10980453
  121. Giroud, M.; Dietzel, U.; Anselm, L.; Banner, D.; Kuglstatter, A.; Benz, J.; Blanc, J.B.; Gaufreteau, D.; Liu, H.; Lin, X.; Stich, A.; Kuhn, B.; Schuler, F.; Kaiser, M.; Brun, R.; Schirmeister, T.; Kisker, C.; Diederich, F.; Haap, W. Repurposing a library of human cathepsin L ligands: Identification of macrocyclic lactams as potent rhodesain and Trypanosoma brucei inhibitors. J. Med. Chem., 2018, 61(8), 3350-3369. doi: 10.1021/acs.jmedchem.7b01869 PMID: 29590750
  122. Mosi, R.; Baird, I.R.; Cox, J.; Anastassov, V.; Cameron, B.; Skerlj, R.T.; Fricker, S.P. Rhenium inhibitors of Cathepsin B (ReO(SYS)X (Where Y = S, py; X = Cl, Br, SPhOMe- p)): Synthesis and mechanism of inhibition. J. Med. Chem., 2006, 49(17), 5262-5272. doi: 10.1021/jm060357z PMID: 16913715
  123. Mott, B.T.; Ferreira, R.S.; Simeonov, A.; Jadhav, A.; Ang, K.K.H.; Leister, W.; Shen, M.; Silveira, J.T.; Doyle, P.S.; Arkin, M.R.; McKerrow, J.H.; Inglese, J.; Austin, C.P.; Thomas, C.J.; Shoichet, B.K.; Maloney, D.J. Identification and optimization of inhibitors of trypanosomal cysteine proteases: Cruzain, rhodesain, and TbCatB. J. Med. Chem., 2010, 53(1), 52-60. doi: 10.1021/jm901069a PMID: 19908842
  124. Vicik, R.; Hoerr, V.; Glaser, M.; Schultheis, M.; Hansell, E.; McKerrow, J.H.; Holzgrabe, U.; Caffrey, C.R.; Ponte-Sucre, A.; Moll, H.; Stich, A.; Schirmeister, T. Aziridine-2,3-dicarboxylate inhibitors targeting the major cysteine protease of Trypanosoma brucei as lead trypanocidal agents. Bioorg. Med. Chem. Lett., 2006, 16(10), 2753-2757. doi: 10.1016/j.bmcl.2006.02.026 PMID: 16516467
  125. Ettari, R.; Previti, S.; Maiorana, S.; Allegra, A.; Schirmeister, T.; Grasso, S.; Zappalà, M. Drug combination studies of curcumin and genistein against rhodesain of Trypanosoma brucei rhodesiense. Nat. Prod. Res., 2019, 33(24), 3577-3581. doi: 10.1080/14786419.2018.1483927 PMID: 29897253
  126. Lavrado, J.; Mackey, Z.; Hansell, E.; McKerrow, J.H.; Paulo, A.; Moreira, R. Anti trypanosomal and cysteine protease inhibitory activities of alkyldiamine cryptolepine derivatives. Bioorg. Med. Chem. Lett., 2012, 22(19), 6256-6260. doi: 10.1016/j.bmcl.2012.07.104 PMID: 22926067
  127. Mallari, J.P.; Shelat, A.A.; Obrien, T.; Caffrey, C.R.; Kosinski, A.; Connelly, M.; Harbut, M.; Greenbaum, D.; McKerrow, J.H.; Guy, R.K. Development of potent purine-derived nitrile inhibitors of the trypanosomal protease TbcatB. J. Med. Chem., 2008, 51(3), 545-552. doi: 10.1021/jm070760l PMID: 18173229
  128. Mallari, J.P.; Shelat, A.A.; Kosinski, A.; Caffrey, C.R.; Connelly, M.; Zhu, F.; McKerrow, J.H.; Guy, R.K. Structure-guided development of selective TbcatB inhibitors. J. Med. Chem., 2009, 52(20), 6489-6493. doi: 10.1021/jm900908p PMID: 19769357
  129. Braga, S.F.P.; Santos, V.C.; Vieira, R.P.; Silva, E.B.; Monti, L.; Krake, S.H.; Martinez, P.D.G.; Dias, L.C.; Caffrey, C.R.; Siqueira-Neto, J.L.; de Oliveira, R.B.; Ferreira, R.S. From rational design to serendipity: Discovery of novel thiosemicarbazones as potent trypanocidal compounds. Eur. J. Med. Chem., 2022, 244, 114876. doi: 10.1016/j.ejmech.2022.114876 PMID: 36343429
  130. Romero, E.L.; Morilla, M.J. Nanotechnological approaches against Chagas disease. Adv. Drug Deliv. Rev., 2010, 62(4-5), 576-588. doi: 10.1016/j.addr.2009.11.025 PMID: 19941920
  131. Figueiredo da Silva, A.A.; Vieira, L.C.; Krieger, M.A.; Goldenberg, S.; Zanchin, N.I.T.; Guimarães, B.G. Crystal structure of chagasin, the endogenous cysteine-protease inhibitor from Trypanosoma cruzi. J. Struct. Biol., 2007, 157(2), 416-423. doi: 10.1016/j.jsb.2006.07.017 PMID: 17011790
  132. Brak, K.; Doyle, P.S.; McKerrow, J.H.; Ellman, J.A. Identification of a new class of nonpeptidic inhibitors of cruzain. J. Am. Chem. Soc., 2008, 130(20), 6404-6410. doi: 10.1021/ja710254m PMID: 18435536
  133. McKerrow, J.; Engel, J.C.; Caffrey, C.R. Cysteine protease inhibitors as chemotherapy for parasitic infections. Bioorg. Med. Chem., 1999, 7(4), 639-644. doi: 10.1016/S0968-0896(99)00008-5 PMID: 10353643
  134. Silva, J.R.A.; Cianni, L.; Araujo, D.; Batista, P.H.J.; de Vita, D.; Rosini, F.; Leitão, A.; Lameira, J.; Montanari, C.A. Assessment of the cruzain cysteine protease reversible and irreversible covalent inhibition mechanism. J. Chem. Inf. Model., 2020, 60(3), 1666-1677. doi: 10.1021/acs.jcim.9b01138 PMID: 32126170
  135. Boudreau, P.D.; Miller, B.W.; McCall, L.I.; Almaliti, J.; Reher, R.; Hirata, K.; Le, T.; Siqueira-Neto, J.L.; Hook, V.; Gerwick, W.H. Design of gallinamide A analogs as potent inhibitors of the cysteine proteases human cathepsin L and Trypanosoma cruzi cruzain. J. Med. Chem., 2019, 62(20), 9026-9044. doi: 10.1021/acs.jmedchem.9b00294 PMID: 31539239
  136. Ferreira, R.S.; Dessoy, M.A.; Pauli, I.; Souza, M.L.; Krogh, R.; Sales, A.I.L.; Oliva, G.; Dias, L.C.; Andricopulo, A.D. Synthesis, biological evaluation, and structure-activity relationships of potent noncovalent and nonpeptidic cruzain inhibitors as anti-Trypanosoma cruzi agents. J. Med. Chem., 2014, 57(6), 2380-2392. doi: 10.1021/jm401709b PMID: 24533839
  137. Yang, P.Y.; Wang, M.; Li, L.; Wu, H.; He, C.Y.; Yao, S.Q. Design, synthesis and biological evaluation of potent azadipeptide nitrile inhibitors and activity-based probes as promising anti-Trypanosoma brucei agents. Chemistry, 2012, 18(21), 6528-6541. doi: 10.1002/chem.201103322 PMID: 22488888
  138. Brak, K.; Kerr, I.D.; Barrett, K.T.; Fuchi, N.; Debnath, M.; Ang, K.; Engel, J.C.; McKerrow, J.H.; Doyle, P.S.; Brinen, L.S.; Ellman, J.A. Nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors as promising new leads for Chagas disease chemotherapy. J. Med. Chem., 2010, 53(4), 1763-1773. doi: 10.1021/jm901633v PMID: 20088534
  139. Chen, Y.T.; Brinen, L.S.; Kerr, I.D.; Hansell, E.; Doyle, P.S.; McKerrow, J.H.; Roush, W.R. In vitro and in vivo studies of the trypanocidal properties of WRR-483 against Trypanosoma cruzi. PLoS Negl. Trop. Dis., 2010, 4(9), e825. doi: 10.1371/journal.pntd.0000825 PMID: 20856868
  140. Trossini, G.H.G.; Malvezzi, A. T-do Amaral, A.; Rangel-Yagui, C.O.; Izidoro, M.A.; Cezari, M.H.; Juliano, L.; Chin, C.M.; Menezes, C.M.; Ferreira, E.I. Cruzain inhibition by hydroxymethylnitrofurazone and nitrofurazone: Investigation of a new target in Trypanosoma cruzi. J. Enzyme Inhib. Med. Chem., 2010, 25(1), 62-67. doi: 10.3109/14756360902941058 PMID: 20030510
  141. Choe, Y.; Brinen, L.S.; Price, M.S.; Engel, J.C.; Lange, M.; Grisostomi, C.; Weston, S.G.; Pallai, P.V.; Cheng, H.; Hardy, L.W.; Hartsough, D.S.; McMakin, M.; Tilton, R.F.; Baldino, C.M.; Craik, C.S. Development of α-keto-based inhibitors of cruzain, a cysteine protease implicated in Chagas disease. Bioorg. Med. Chem., 2005, 13(6), 2141-2156. doi: 10.1016/j.bmc.2004.12.053 PMID: 15727867
  142. Greenbaum, D.C.; Mackey, Z.; Hansell, E.; Doyle, P.; Gut, J.; Caffrey, C.R.; Lehrman, J.; Rosenthal, P.J.; McKerrow, J.H.; Chibale, K. Synthesis and structure-activity relationships of parasiticidal thiosemicarbazone cysteine protease inhibitors against Plasmodium falciparum, Trypanosoma brucei, and Trypanosoma cruzi. J. Med. Chem., 2004, 47(12), 3212-3219. doi: 10.1021/jm030549j PMID: 15163200

Supplementary files

Supplementary Files
Action
1. JATS XML

Copyright (c) 2024 Bentham Science Publishers