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Current Medicinal Chemistry

Author(s): Rafael Pinto Vieira, Viviane Corrêa Santos and Rafaela Salgado Ferreira*

DOI: 10.2174/0929867324666170810165302

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Structure-based Approaches Targeting Parasite Cysteine Proteases

Page: [4435 - 4453] Pages: 19

  • * (Excluding Mailing and Handling)

Abstract

Cysteine proteases are essential hydrolytic enzymes present in the majority of organisms, including viruses and unicellular parasites. Despite the high sequence identity displayed among these proteins, specific structural features across different species grant distinct functions to these biomolecules, frequently related to pathological conditions. Consequently, their relevance as promising targets for potential specific inhibitors has been highlighted and occasionally validated in recent decades. In this review, we discuss the recent outcomes of structure-based campaigns aiming the discovery of new inhibitor prototypes against cruzain and falcipain, as alternative therapeutic tools for Chagas disease and malaria treatments, respectively. Computational and synthetic approaches have been combined on hit optimization strategies and are also discussed herein. These rationales are extended to additional tropical infectious and neglected pathologies, such as schistosomiasis, leishmaniasis and babesiosis, and also to Alzheimer’s Disease, a widespread neurodegenerative disease poorly managed by currently available drugs and recently linked to particular physiopathological roles of human cysteine proteases.

Keywords: Structure-based strategies, cysteine proteases, cruzain, falcipain, human cathepsins, tropical infectious diseases, Alzheimer's Disease.

[1]
Costa, T.F.; Lima, A.P. Natural cysteine protease inhibitors in protozoa: Fifteen years of the chagasin family. Biochimie, 2016, 122, 197-207.
[http://dx.doi.org/10.1016/j.biochi.2015.11.002] [PMID: 26546840]
[2]
McKerrow, J.H.; Caffrey, C.; Kelly, B.; Loke, P.; Sajid, M. Proteases in parasitic diseases. Annu. Rev. Pathol., 2006, 1, 497-536.
[http://dx.doi.org/10.1146/annurev.pathol.1.110304.100151] [PMID: 18039124]
[3]
McKerrow, J.H.; Rosenthal, P.J.; Swenerton, R.; Doyle, P. Development of protease inhibitors for protozoan infections. Curr. Opin. Infect. Dis., 2008, 21(6), 668-672.
[http://dx.doi.org/10.1097/QCO.0b013e328315cca9] [PMID: 18978536]
[4]
Rosenthal, P.J.; Wollish, W.S.; Palmer, J.T.; Rasnick, D. Antimalarial effects of peptide inhibitors of a Plasmodium falciparum cysteine proteinase. J. Clin. Invest., 1991, 88(5), 1467-1472.
[http://dx.doi.org/10.1172/JCI115456] [PMID: 1939639]
[5]
Rosenthal, P.J.; Lee, G.K.; Smith, R.E. Inhibition of a Plasmodium vinckei cysteine proteinase cures murine malaria. J. Clin. Invest., 1993, 91(3), 1052-1056.
[http://dx.doi.org/10.1172/JCI116262] [PMID: 8450035]
[6]
Rosenthal, P.J.; Olson, J.E.; Lee, G.K.; Palmer, J.T.; Klaus, J.L.; Rasnick, D. Antimalarial effects of vinyl sulfone cysteine proteinase inhibitors. Antimicrob. Agents Chemother., 1996, 40(7), 1600-1603.
[http://dx.doi.org/10.1128/AAC.40.7.1600] [PMID: 8807047]
[7]
Engel, J.C.; Doyle, P.S.; Hsieh, I.; McKerrow, J.H. Cysteine protease inhibitors cure an experimental Trypanosoma cruzi infection. J. Exp. Med., 1998, 188(4), 725-734.
[http://dx.doi.org/10.1084/jem.188.4.725] [PMID: 9705954]
[8]
Lecaille, F.; Kaleta, J.; Brömme, D. Human and parasitic papain-like cysteine proteases: their role in physiology and pathology and recent developments in inhibitor design. Chem. Rev., 2002, 102(12), 4459-4488.
[http://dx.doi.org/10.1021/cr0101656] [PMID: 12475197]
[9]
Lima, A.P.; Reis, F.C.; Costa, T.F. Cysteine peptidase inhibitors in trypanosomatid parasites. Curr. Med. Chem., 2013, 20(25), 3152-3173.
[http://dx.doi.org/10.2174/0929867311320250009] [PMID: 23514421]
[10]
Schmunis, G.A. Epidemiology of Chagas disease in non-endemic countries: The role of international migration. Mem. Inst. Oswaldo Cruz, 2007, 102(Suppl. 1), 75-85.
[http://dx.doi.org/10.1590/S0074-02762007005000093] [PMID: 17891282]
[11]
Gascon, J.; Bern, C.; Pinazo, M.J. Chagas disease in Spain, the United States and other non-endemic countries. Acta Trop., 2010, 115(1-2), 22-27.
[http://dx.doi.org/10.1016/j.actatropica.2009.07.019] [PMID: 19646412]
[12]
Roca, C.; Pinazo, M.J.; López-Chejade, P.; Bayó, J.; Posada, E.; López-Solana, J.; Gállego, M.; Portús, M.; Gascón, J. Chagas-Clot Research Group. Chagas disease among the Latin American adult population attending in a primary care center in Barcelona, Spain. PLoS Negl. Trop. Dis., 2011, 5(4)e1135
[http://dx.doi.org/10.1371/journal.pntd.0001135] [PMID: 21572511]
[13]
World Health Organization (WHO). Chagas disease (American trypanosomiasis).. http://www.who.int/mediacentre/factsheets/fs340/en/ (Accessed September 02, 2016).
[14]
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.
[http://dx.doi.org/10.1128/CMR.00005-11] [PMID: 21976603]
[15]
Albajar-Vinas, P.; Jannin, J. The hidden Chagas disease burden in Europe. Euro surveillance: European communicable disease bulletin., 2011, 16(38), 19975.
[http://dx.doi.org/10.2807/ese.16.38.19975-en]
[16]
Garza, M.; Feria Arroyo, T.P.; Casillas, E.A.; Sanchez-Cordero, V.; Rivaldi, C.L.; Sarkar, S. Projected future distributions of vectors of Trypanosoma cruzi in North America under climate change scenarios. PLoS Negl. Trop. Dis., 2014, 8(5)e2818
[http://dx.doi.org/10.1371/journal.pntd.0002818] [PMID: 24831117]
[17]
Patz, J.A.; Graczyk, T.K.; Geller, N.; Vittor, A.Y. Effects of environmental change on emerging parasitic diseases. Int. J. Parasitol., 2000, 30(12-13), 1395-1405.
[http://dx.doi.org/10.1016/S0020-7519(00)00141-7] [PMID: 11113264]
[18]
Lafferty, K.D. The ecology of climate change and infectious diseases. Ecology, 2009, 90(4), 888-900.
[http://dx.doi.org/10.1890/08-0079.1] [PMID: 19449681]
[19]
Cazzulo, J.J.; Stoka, V.; Turk, V. Cruzipain, the major cysteine proteinase from the protozoan parasite Trypanosoma cruzi. Biol. Chem., 1997, 378(1), 1-10.
[PMID: 9049059]
[20]
da Silva, E.B.; do Nascimento Pereira, G.A.; Ferreira, R.S. Trypanosomal cysteine peptidases: Target validation and drug design strategies. In: Comprehensive Analysis of Parasite Biology: From Metabolism to Drug Discovery; Wiley- VCH Verlag GmbH & Co. KGaA, 2016; pp. 121-145.
[21]
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.
[http://dx.doi.org/10.1006/jmbi.1994.0137] [PMID: 7707373]
[22]
World Health Organization (WHO). Fact Sheet: World Malaria Report 2015. http://www.who.int/malaria/media/world-malaria-report-2015/en/ (Accessed September 01, 2016).
[23]
Rosenthal, P.J. Falcipains and other cysteine proteases of malaria parasites. Adv. Exp. Med. Biol., 2011, 712, 30-48.
[http://dx.doi.org/10.1007/978-1-4419-8414-2_3] [PMID: 21660657]
[24]
Asawamahasakda, W.; Ittarat, I.; Chang, C.C.; McElroy, P.; Meshnick, S.R. Effects of antimalarials and protease inhibitors on plasmodial hemozoin production. Mol. Biochem. Parasitol., 1994, 67(2), 183-191.
[http://dx.doi.org/10.1016/0166-6851(94)00128-6] [PMID: 7870123]
[25]
Gamboa de Domínguez, N.D.; Rosenthal, P.J. Cysteine proteinase inhibitors block early steps in hemoglobin degradation by cultured malaria parasites. Blood, 1996, 87(10), 4448-4454.
[PMID: 8639807]
[26]
Mane, U.R.; Gupta, R.C.; Nadkarni, S.S.; Giridhar, R.R.; Naik, P.P.; Yadav, M.R. Falcipain inhibitors as potential therapeutics for resistant strains of malaria: a patent review. Expert Opin. Ther. Pat., 2013, 23(2), 165-187.
[http://dx.doi.org/10.1517/13543776.2013.743992]
[27]
DiMasi, J.A.; Grabowski, H.G.; Hansen, R.W. Innovation in the pharmaceutical industry: New estimates of R&D costs. J. Health Econ., 2016, 47, 20-33.
[http://dx.doi.org/10.1016/j.jhealeco.2016.01.012] [PMID: 26928437]
[28]
Shenai, B.R.; Lee, B.J.; Alvarez-Hernandez, A.; Chong, P.Y.; Emal, C.D.; Neitz, R.J.; Roush, W.R.; Rosenthal, P.J. Structure-activity relationships for inhibition of cysteine protease activity and development of Plasmodium falciparum by peptidyl vinyl sulfones. Antimicrob. Agents Chemother., 2003, 47(1), 154-160.
[http://dx.doi.org/10.1128/AAC.47.1.154-160.2003] [PMID: 12499184]
[29]
Ripphausen, P.; Nisius, B.; Peltason, L.; Bajorath, J. Quo vadis, virtual screening? A comprehensive survey of prospective applications. J. Med. Chem., 2010, 53(24), 8461-8467.
[http://dx.doi.org/10.1021/jm101020z] [PMID: 20929257]
[30]
Wang, L.; Zhang, S.; Zhu, J.; Zhu, L.; Liu, X.; Shan, L.; Huang, J.; Zhang, W.; Li, H. Identification of diverse natural products as falcipain-2 inhibitors through structure-based virtual screening. Bioorg. Med. Chem. Lett., 2014, 24(5), 1261-1264.
[http://dx.doi.org/10.1016/j.bmcl.2014.01.074] [PMID: 24530004]
[31]
Chakka, S.K.; Kalamuddin, M.; Sundararaman, S.; Wei, L.; Mundra, S.; Mahesh, R.; Malhotra, P.; Mohmmed, A.; Kotra, L.P. Identification of novel class of falcipain-2 inhibitors as potential antimalarial agents. Bioorg. Med. Chem., 2015, 23(9), 2221-2240.
[http://dx.doi.org/10.1016/j.bmc.2015.02.062] [PMID: 25840796]
[32]
Shah, F.; Mukherjee, P.; Gut, J.; Legac, J.; Rosenthal, P.J.; Tekwani, B.L.; Avery, M.A. Identification of novel malarial cysteine protease inhibitors using structure-based virtual screening of a focused cysteine protease inhibitor library. J. Chem. Inf. Model., 2011, 51(4), 852-864.
[http://dx.doi.org/10.1021/ci200029y] [PMID: 21428453]
[33]
Wiggers, H.J.; Rocha, J.R.; Fernandes, W.B.; Sesti-Costa, R.; Carneiro, Z.A.; Cheleski, J.; da Silva, A.B.; Juliano, L.; Cezari, M.H.; Silva, J.S.; McKerrow, J.H.; Montanari, C.A. Non-peptidic cruzain inhibitors with trypanocidal activity discovered by virtual screening and in vitro assay. PLoS Negl. Trop. Dis., 2013, 7(8)e2370
[http://dx.doi.org/10.1371/journal.pntd.0002370] [PMID: 23991231]
[34]
Mugumbate, G.; Newton, A.S.; Rosenthal, P.J.; Gut, J.; Moreira, R.; Chibale, K.; Guedes, R.C. Novel anti-plasmodial hits identified by virtual screening of the ZINC database. J. Comput. Aided Mol. Des., 2013, 27(10), 859-871.
[http://dx.doi.org/10.1007/s10822-013-9685-z] [PMID: 24158745]
[35]
Rogers, K.E.; Keränen, H.; Durrant, J.D.; Ratnam, J.; Doak, A.; Arkin, M.R.; McCammon, J.A. Novel cruzain inhibitors for the treatment of Chagas’ disease. Chem. Biol. Drug Des., 2012, 80(3), 398-405.
[http://dx.doi.org/10.1111/j.1747-0285.2012.01416.x] [PMID: 22613098]
[36]
Ferreira, R.S.; Simeonov, A.; Jadhav, A.; Eidam, O.; Mott, B.T.; Keiser, M.J.; McKerrow, J.H.; Maloney, D.J.; Irwin, J.J.; Shoichet, B.K. Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors. J. Med. Chem., 2010, 53(13), 4891-4905.
[http://dx.doi.org/10.1021/jm100488w] [PMID: 20540517]
[37]
Shah, F.; Gut, J.; Legac, J.; Shivakumar, D.; Sherman, W.; Rosenthal, P.J.; Avery, M.A. Computer-aided drug design of falcipain inhibitors: virtual screening, structure-activity relationships, hydration site thermodynamics, and reactivity analysis. J. Chem. Inf. Model., 2012, 52(3), 696-710.
[http://dx.doi.org/10.1021/ci2005516] [PMID: 22332946]
[38]
Ferreira, R.S.; Dessoy, M.A.; Pauli, I.; Souza, M.L.; Krogh, R.; Sales, A.I.; 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.
[http://dx.doi.org/10.1021/jm401709b] [PMID: 24533839]
[39]
Sabnis, Y.; Rosenthal, P.J.; Desai, P.; Avery, M.A. Homology modeling of falcipain-2: validation, de novo ligand design and synthesis of novel inhibitors. J. Biomol. Struct. Dyn., 2002, 19(5), 765-774.
[http://dx.doi.org/10.1080/07391102.2002.10506783] [PMID: 11922834]
[40]
Weldon, D.J.; Shah, F.; Chittiboyina, A.G.; Sheri, A.; Chada, R.R.; Gut, J.; Rosenthal, P.J.; Shivakumar, D.; Sherman, W.; Desai, P.; Jung, J.C.; Avery, M.A. Synthesis, biological evaluation, hydration site thermodynamics, and chemical reactivity analysis of α-keto substituted peptidomimetics for the inhibition of Plasmodium falciparum. Bioorg. Med. Chem. Lett., 2014, 24(5), 1274-1279.
[http://dx.doi.org/10.1016/j.bmcl.2014.01.062] [PMID: 24507921]
[41]
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem., 2004, 47(7), 1739-1749.
[http://dx.doi.org/10.1021/jm0306430] [PMID: 15027865]
[42]
Friesner, R.A.; Murphy, R.B.; Repasky, M.P.; Frye, L.L.; Greenwood, J.R.; Halgren, T.A.; Sanschagrin, P.C.; Mainz, D.T. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem., 2006, 49(21), 6177-6196.
[http://dx.doi.org/10.1021/jm051256o] [PMID: 17034125]
[43]
Kerr, I.D.; Lee, J.H.; Pandey, K.C.; Harrison, A.; Sajid, M.; Rosenthal, P.J.; Brinen, L.S. Structures of falcipain-2 and falcipain-3 bound to small molecule inhibitors: implications for substrate specificity. J. Med. Chem., 2009, 52(3), 852-857.
[http://dx.doi.org/10.1021/jm8013663] [PMID: 19128015]
[44]
Bruce-Chwatt, L.J. Three hundred and fifty years of the Peruvian fever bark. Br. Med. J. (Clin. Res. Ed.), 1988, 296(6635), 1486-1487.
[http://dx.doi.org/10.1136/bmj.296.6635.1486] [PMID: 3134079]
[45]
Jin, H.; Xu, Z.; Cui, K.; Zhang, T.; Lu, W.; Huang, J. Dietary flavonoids fisetin and myricetin: dual inhibitors of Plasmodium falciparum falcipain-2 and plasmepsin II. Fitoterapia, 2014, 94, 55-61.
[http://dx.doi.org/10.1016/j.fitote.2014.01.017] [PMID: 24468190]
[46]
Le Bonniec, S.; Deregnaucourt, C.; Redeker, V.; Banerjee, R.; Grellier, P.; Goldberg, D.E.; Schrével, J. Plasmepsin II, an acidic hemoglobinase from the Plasmodium falciparum food vacuole, is active at neutral pH on the host erythrocyte membrane skeleton. J. Biol. Chem., 1999, 274(20), 14218-14223.
[http://dx.doi.org/10.1074/jbc.274.20.14218] [PMID: 10318841]
[47]
Hanspal, M.; Dua, M.; Takakuwa, Y.; Chishti, A.H.; Mizuno, A. Plasmodium falciparum cysteine protease falcipain-2 cleaves erythrocyte membrane skeletal proteins at late stages of parasite development. Blood, 2002, 100(3), 1048-1054.
[http://dx.doi.org/10.1182/blood-2002-01-0101] [PMID: 12130521]
[48]
Dhawan, S.; Dua, M.; Chishti, A.H.; Hanspal, M. Ankyrin peptide blocks falcipain-2-mediated malaria parasite release from red blood cells. J. Biol. Chem., 2003, 278(32), 30180-30186.
[http://dx.doi.org/10.1074/jbc.M305132200] [PMID: 12775709]
[49]
Kerr, I.D.; Lee, J.H.; Farady, C.J.; Marion, R.; Rickert, M.; Sajid, M.; Pandey, K.C.; Caffrey, C.R.; Legac, J.; Hansell, E.; McKerrow, J.H.; Craik, C.S.; Rosenthal, P.J.; Brinen, L.S. Vinyl sulfones as antiparasitic agents and a structural basis for drug design. J. Biol. Chem., 2009, 284(38), 25697-25703.
[http://dx.doi.org/10.1074/jbc.M109.014340] [PMID: 19620707]
[50]
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
[http://dx.doi.org/10.1371/journal.pntd.0000825] [PMID: 20856868]
[51]
Jones, B.D.; Tochowicz, A.; Tang, Y.; Cameron, M.D.; McCall, L.I.; Hirata, K.; Siqueira-Neto, J.L.; Reed, S.L.; McKerrow, J.H.; Roush, W.R. Synthesis and evaluation of oxyguanidine analogues of the cysteine protease inhibitor WRR-483 against Cruzain. ACS Med. Chem. Lett., 2015, 7(1), 77-82.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00336] [PMID: 26819670]
[52]
Oliveira, R.; Newton, A.S.; Guedes, R.C.; Miranda, D.; Amewu, R.K.; Srivastava, A.; Gut, J.; Rosenthal, P.J.; O’Neill, P.M.; Ward, S.A.; Lopes, F.; Moreira, R. An endoperoxide-based hybrid approach to deliver falcipain inhibitors inside malaria parasites. ChemMedChem, 2013, 8(9), 1528-1536.
[http://dx.doi.org/10.1002/cmdc.201300202] [PMID: 23853126]
[53]
Oliveira, R.; Guedes, R.C.; Meireles, P.; Albuquerque, I.S.; Gonçalves, L.M.; Pires, E.; Bronze, M.R.; Gut, J.; Rosenthal, P.J.; Prudêncio, M.; Moreira, R.; O’Neill, P.M.; Lopes, F. Tetraoxane-pyrimidine nitrile hybrids as dual stage antimalarials. J. Med. Chem., 2014, 57(11), 4916-4923.
[http://dx.doi.org/10.1021/jm5004528] [PMID: 24824551]
[54]
Capela, R.; Oliveira, R.; Gonçalves, L.M.; Domingos, A.; Gut, J.; Rosenthal, P.J.; Lopes, F.; Moreira, R. Artemisinin-dipeptidyl vinyl sulfone hybrid molecules: design, synthesis and preliminary SAR for antiplasmodial activity and falcipain-2 inhibition. Bioorg. Med. Chem. Lett., 2009, 19(12), 3229-3232.
[http://dx.doi.org/10.1016/j.bmcl.2009.04.100] [PMID: 19435664]
[55]
O’Neill, P.M.; Posner, G.H. A medicinal chemistry perspective on artemisinin and related endoperoxides. J. Med. Chem., 2004, 47(12), 2945-2964.
[http://dx.doi.org/10.1021/jm030571c] [PMID: 15163175]
[56]
Coslédan, F.; Fraisse, L.; Pellet, A.; Guillou, F.; Mordmüller, B.; Kremsner, P.G.; Moreno, A.; Mazier, D.; Maffrand, J.P.; Meunier, B. Selection of a trioxaquine as an antimalarial drug candidate. Proc. Natl. Acad. Sci. USA, 2008, 105(45), 17579-17584.
[http://dx.doi.org/10.1073/pnas.0804338105] [PMID: 18987321]
[57]
Capela, R.; Cabal, G.G.; Rosenthal, P.J.; Gut, J.; Mota, M.M.; Moreira, R.; Lopes, F.; Prudêncio, M. Design and evaluation of primaquine-artemisinin hybrids as a multistage antimalarial strategy. Antimicrob. Agents Chemother., 2011, 55(10), 4698-4706.
[http://dx.doi.org/10.1128/AAC.05133-11] [PMID: 21807973]
[58]
Slack, R.D.; Jacobine, A.M.; Posner, G.H. Antimalarial peroxides: Advances in drug discovery and design. MedChemComm, 2012, 3(3), 281-297.
[http://dx.doi.org/10.1039/c2md00277a]
[59]
Altmann, E.; Cowan-Jacob, S.W.; Missbach, M. Novel purine nitrile derived inhibitors of the cysteine protease cathepsin K. J. Med. Chem., 2004, 47(24), 5833-5836.
[http://dx.doi.org/10.1021/jm0493111] [PMID: 15537340]
[60]
Greenspan, P.D.; Clark, K.L.; Cowen, S.D.; McQuire, L.W.; Tommasi, R.A.; Farley, D.L.; Quadros, E.; Coppa, D.E.; Du, Z.; Fang, Z.; Zhou, H.; Doughty, J.; Toscano, K.T.; Wigg, A.M.; Zhou, S. N-arylaminonitriles as bioavailable peptidomimetic inhibitors of cathepsin B. Bioorg. Med. Chem. Lett., 2003, 13(22), 4121-4124.
[http://dx.doi.org/10.1016/j.bmcl.2003.08.006] [PMID: 14592520]
[61]
Mott, B.T.; Ferreira, R.S.; Simeonov, A.; Jadhav, A.; Ang, K.K.; 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.
[http://dx.doi.org/10.1021/jm901069a] [PMID: 19908842]
[62]
Ehmke, V.; Heindl, C.; Rottmann, M.; Freymond, C.; Schweizer, W.B.; Brun, R.; Stich, A.; Schirmeister, T.; Diederich, F. Potent and selective inhibition of cysteine proteases from Plasmodium falciparum and Trypanosoma brucei. ChemMedChem, 2011, 6(2), 273-278.
[http://dx.doi.org/10.1002/cmdc.201000449] [PMID: 21275051]
[63]
Ehmke, V.; Quinsaat, J.E.; Rivera-Fuentes, P.; Heindl, C.; Freymond, C.; Rottmann, M.; Brun, R.; Schirmeister, T.; Diederich, F. Tuning and predicting biological affinity: aryl nitriles as cysteine protease inhibitors. Org. Biomol. Chem., 2012, 10(30), 5764-5768.
[http://dx.doi.org/10.1039/c2ob00034b] [PMID: 22336919]
[64]
World Health Organization (WHO). Schistosomiasis. http://www.who.int/schistosomiasis/en/ (Accessed September 02, 2016)
[65]
Jílková, A.; Rezácová, P.; Lepsík, M.; Horn, M.; Váchová, J.; Fanfrlík, J.; Brynda, J.; McKerrow, J.H.; Caffrey, C.R.; Mares, M. Structural basis for inhibition of cathepsin B drug target from the human blood fluke, Schistosoma mansoni. J. Biol. Chem., 2011, 286(41), 35770-35781.
[http://dx.doi.org/10.1074/jbc.M111.271304] [PMID: 21832058]
[66]
Fonseca, N.C.; da Cruz, L.F.; da Silva Villela, F.; do Nascimento Pereira, G.A.; de Siqueira-Neto, J.L.; Kellar, D.; Suzuki, B.M.; Ray, D.; de Souza, T.B.; Alves, R.J.; Sales Júnior, P.A.; Romanha, A.J.; Murta, S.M.; McKerrow, J.H.; Caffrey, C.R.; de Oliveira, R.B.; Ferreira, R.S. Synthesis of a sugar-based thiosemicarbazone series and structure-activity relationship versus the parasite cysteine proteases rhodesain, cruzain, and Schistosoma mansoni cathepsin B1. Antimicrob. Agents Chemother., 2015, 59(5), 2666-2677.
[http://dx.doi.org/10.1128/AAC.04601-14] [PMID: 25712353]
[67]
Olson, J.E.; Lee, G.K.; Semenov, A.; Rosenthal, P.J. Antimalarial effects in mice of orally administered peptidyl cysteine protease inhibitors. Bioorg. Med. Chem., 1999, 7(4), 633-638.
[http://dx.doi.org/10.1016/S0968-0896(99)00004-8] [PMID: 10353642]
[68]
Fanfrlík, J.; Brahmkshatriya, P.S.; Řezáč, J.; Jílková, A.; Horn, M.; Mareš, M.; Hobza, P.; Lepšík, M. Quantum mechanics-based scoring rationalizes the irreversible inactivation of parasitic Schistosoma mansoni cysteine peptidase by vinyl sulfone inhibitors. J. Phys. Chem. B, 2013, 117(48), 14973-14982.
[http://dx.doi.org/10.1021/jp409604n] [PMID: 24195769]
[69]
World Health Organization (WHO). Leishmaniasis.. http://www.who.int/leishmaniasis/en/ (Accessed September 02, 2016)
[70]
Schröder, J.; Noack, S.; Marhöfer, R.J.; Mottram, J.C.; Coombs, G.H.; Selzer, P.M. Identification of semicarbazones, thiosemicarbazones and triazine nitriles as inhibitors of Leishmania mexicana cysteine protease CPB. PLoS One, 2013, 8(10)e77460
[http://dx.doi.org/10.1371/journal.pone.0077460] [PMID: 24146999]
[71]
Du, X.; Guo, C.; Hansell, E.; Doyle, P.S.; Caffrey, C.R.; Holler, T.P.; McKerrow, J.H.; Cohen, F.E. Synthesis and structure-activity relationship study of potent trypanocidal thio semicarbazone inhibitors of the trypanosomal cysteine protease cruzain. J. Med. Chem., 2002, 45(13), 2695-2707.
[http://dx.doi.org/10.1021/jm010459j] [PMID: 12061873]
[72]
Vital, D.G.; Damasceno, F.S.; Rapado, L.N.; Silber, A.M.; Vilella, F.S.; Ferreira, R.S.; Maltarollo, V.G.; Trossini, G.H. Application of bioisosterism in design of the semicarbazone derivatives as cruzain inhibitors: A theoretical and experimental study. J. Biomol. Struct. Dyn., 2016, 1-16.
[PMID: 27064715]
[73]
Centers for Disease Control and Prevention (CDC). Parasites - Babesiosis. www.cdc.gov/parasites/babesiosis (Accessed September 04, 2016).
[74]
de Waal, D.T.; Combrink, M.P. Live vaccines against bovine babesiosis. Vet. Parasitol., 2006, 138(1-2), 88-96.
[http://dx.doi.org/10.1016/j.vetpar.2006.01.042] [PMID: 16504404]
[75]
Fish, L.; Leibovich, B.; Krigel, Y.; McElwain, T.; Shkap, V. Vaccination of cattle against B. bovis infection with live attenuated parasites and non-viable immunogens. Vaccine, 2008, 26(Suppl. 6), G29-G33.
[http://dx.doi.org/10.1016/j.vaccine.2008.09.070] [PMID: 19178890]
[76]
Schnittger, L.; Rodriguez, A.E.; Florin-Christensen, M.; Morrison, D.A. Babesia: a world emerging. Infect. Genet. Evol., 2012, 12(8), 1788-1809.
[http://dx.doi.org/10.1016/j.meegid.2012.07.004]
[77]
Okubo, K.; Yokoyama, N.; Govind, Y.; Alhassan, A.; Igarashi, I. Babesia bovis: Effects of cysteine protease inhibitors on in vitro growth. Exp. Parasitol., 2007, 117(2), 214-217.
[http://dx.doi.org/10.1016/j.exppara.2007.04.009] [PMID: 17543303]
[78]
Martins, T.M.; do Rosário, V.E.; Domingos, A. Identification of papain-like cysteine proteases from the bovine piroplasm Babesia bigemina and evolutionary relationship of piroplasms C1 family of cysteine proteases. Exp. Parasitol., 2011, 127(1), 184-194.
[http://dx.doi.org/10.1016/j.exppara.2010.07.012] [PMID: 20655912]
[79]
Pérez, B.; Antunes, S.; Gonçalves, L.M.; Domingos, A.; Gomes, J.R.; Gomes, P.; Teixeira, C. Toward the discovery of inhibitors of babesipain-1, a Babesia bigemina cysteine protease: In vitro evaluation, homology modeling and molecular docking studies. J. Comput. Aided Mol. Des., 2013, 27(9), 823-835.
[http://dx.doi.org/10.1007/s10822-013-9682-2] [PMID: 24129820]
[80]
Pérez, B.C.; Teixeira, C.; Figueiras, M.; Gut, J.; Rosenthal, P.J.; Gomes, J.R.; Gomes, P. Novel cinnamic acid/4-aminoquinoline conjugates bearing non-proteinogenic amino acids: towards the development of potential dual action antimalarials. Eur. J. Med. Chem., 2012, 54, 887-899.
[http://dx.doi.org/10.1016/j.ejmech.2012.05.022] [PMID: 22683112]
[81]
Ndao, M.; Nath-Chowdhury, M.; Sajid, M.; Marcus, V.; Mashiyama, S.T.; Sakanari, J.; Chow, E.; Mackey, Z.; Land, K.M.; Jacobson, M.P.; Kalyanaraman, C.; McKerrow, J.H.; Arrowood, M.J.; Caffrey, C.R. A cysteine protease inhibitor rescues mice from a lethal Cryptosporidium parvum infection. Antimicrob. Agents Chemother., 2013, 57(12), 6063-6073.
[http://dx.doi.org/10.1128/AAC.00734-13] [PMID: 24060869]
[82]
Schiefer, I.T.; Tapadar, S.; Litosh, V.; Siklos, M.; Scism, R.; Wijewickrama, G.T.; Chandrasena, E.P.; Sinha, V.; Tavassoli, E.; Brunsteiner, M.; Fa’, M.; Arancio, O.; Petukhov, P.; Thatcher, G.R. Design, synthesis, and optimization of novel epoxide incorporating peptidomimetics as selective calpain inhibitors. J. Med. Chem., 2013, 56(15), 6054-6068.
[http://dx.doi.org/10.1021/jm4006719] [PMID: 23834438]
[83]
Borišek, J.; Vizovišek, M.; Sosnowski, P.; Turk, B.; Turk, D.; Mohar, B.; Novič, M. Development of N-(Functionalized benzoyl)-homocycloleucyl-glycinonitriles as Potent Cathepsin K Inhibitors. J. Med. Chem., 2015, 58(17), 6928-6937.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00746] [PMID: 26280490]
[84]
Grosche, P.; Sirockin, F.; Mac Sweeney, A.; Ramage, P.; Erbel, P.; Melkko, S.; Bernardi, A.; Hughes, N.; Ellis, D.; Combrink, K.D.; Jarousse, N.; Altmann, E. Structure-based design and optimization of potent inhibitors of the adenoviral protease. Bioorg. Med. Chem. Lett., 2015, 25(3), 438-443.
[http://dx.doi.org/10.1016/j.bmcl.2014.12.057] [PMID: 25571794]
[85]
Zhai, Y.; Zhao, X.; Cui, Z.; Wang, M.; Wang, Y.; Li, L.; Sun, Q.; Yang, X.; Zeng, D.; Liu, Y.; Sun, Y.; Lou, Z.; Shang, L.; Yin, Z. Cyanohydrin as an anchoring group for potent and selective inhibitors of enterovirus 71 3C protease. J. Med. Chem., 2015, 58(23), 9414-9420.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01013] [PMID: 26571192]
[86]
World Health Organization (WHO). Fact sheet: Dementia.. http://www.who.int/mediacentre/factsheets/fs362/en/ (Accessed September 02, 2016)
[87]
Holtzman, D.M.; Mandelkow, E.; Selkoe, D.J. Alzheimer disease in 2020. Cold Spring Harb. Perspect. Med., 2012, 2(11)a011585
[http://dx.doi.org/10.1101/cshperspect.a011585] [PMID: 23125202]
[88]
Kidd, M. Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature, 1963, 197, 192-193.
[http://dx.doi.org/10.1038/197192b0] [PMID: 14032480]
[89]
Blennow, K.; de Leon, M.J.; Zetterberg, H. Alzheimer’s disease. Lancet, 2006, 368(9533), 387-403.
[http://dx.doi.org/10.1016/S0140-6736(06)69113-7] [PMID: 16876668]
[90]
Klein, W.L. Synaptotoxic amyloid-β oligomers: a molecular basis for the cause, diagnosis, and treatment of Alzheimer’s disease? J. Alzheimers Dis., 2013, 33(Suppl. 1), S49-S65.
[http://dx.doi.org/10.3233/JAD-2012-129039] [PMID: 22785404]
[91]
Selkoe, D.J.; Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med., 2016, 8(6), 595-608.
[http://dx.doi.org/10.15252/emmm.201606210] [PMID: 27025652]
[92]
Hook, V.Y.; Toneff, T.; Aaron, W.; Yasothornsrikul, S.; Bundey, R.; Reisine, T. Beta-amyloid peptide in regulated secretory vesicles of chromaffin cells: evidence for multiple cysteine proteolytic activities in distinct pathways for beta-secretase activity in chromaffin vesicles. J. Neurochem., 2002, 81(2), 237-256.
[http://dx.doi.org/10.1046/j.1471-4159.2002.00794.x] [PMID: 12064471]
[93]
Hook, V.; Toneff, T.; Bogyo, M.; Greenbaum, D.; Medzihradszky, K.F.; Neveu, J.; Lane, W.; Hook, G.; Reisine, T. Inhibition of cathepsin B reduces beta-amyloid production in regulated secretory vesicles of neuronal chromaffin cells: evidence for cathepsin B as a candidate beta-secretase of Alzheimer’s disease. Biol. Chem., 2005, 386(9), 931-940.
[http://dx.doi.org/10.1515/BC.2005.108] [PMID: 16164418]
[94]
Hook, G.; Hook, V.Y.; Kindy, M. Cysteine protease inhibitors reduce brain beta-amyloid and beta-secretase activity in vivo and are potential Alzheimer’s disease therapeutics. Biol. Chem., 2007, 388(9), 979-983.
[http://dx.doi.org/10.1515/BC.2007.117] [PMID: 17696783]
[95]
Hook, V.; Hook, G.; Kindy, M. Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit and reduce beta-amyloid related to Alzheimer’s disease. Biol. Chem., 2010, 391(8), 861-872.
[http://dx.doi.org/10.1515/bc.2010.110] [PMID: 20536395]
[96]
Hook, V.Y.; Kindy, M.; Hook, G. Inhibitors of cathepsin B improve memory and reduce beta-amyloid in transgenic Alzheimer disease mice expressing the wild-type, but not the Swedish mutant, beta-secretase site of the amyloid precursor protein. J. Biol. Chem., 2008, 283(12), 7745-7753.
[http://dx.doi.org/10.1074/jbc.M708362200] [PMID: 18184658]
[97]
Hook, G.; Hook, V.; Kindy, M. The cysteine protease inhibitor, E64d, reduces brain amyloid-β and improves memory deficits in Alzheimer’s disease animal models by inhibiting cathepsin B, but not BACE1, β-secretase activity. J. Alzheimers Dis., 2011, 26(2), 387-408.
[http://dx.doi.org/10.3233/JAD-2011-110101] [PMID: 21613740]
[98]
Hook, G.; Jacobsen, J.S.; Grabstein, K.; Kindy, M.; Hook, V. Cathepsin B is a New Drug Target for Traumatic Brain Injury Therapeutics: Evidence for E64d as a Promising Lead Drug Candidate. Front. Neurol., 2015, 6, 178.
[http://dx.doi.org/10.3389/fneur.2015.00178] [PMID: 26388830]
[99]
Biswas, N.; Rodriguez-Flores, J.L.; Courel, M.; Gayen, J.R.; Vaingankar, S.M.; Mahata, M.; Torpey, J.W.; Taupenot, L.; O’Connor, D.T.; Mahata, S.K. Cathepsin L colocalizes with chromogranin a in chromaffin vesicles to generate active peptides. Endocrinology, 2009, 150(8), 3547-3557.
[http://dx.doi.org/10.1210/en.2008-1613] [PMID: 19372204]
[100]
Funkelstein, L.; Beinfeld, M.; Minokadeh, A.; Zadina, J.; Hook, V. Unique biological function of cathepsin L in secretory vesicles for biosynthesis of neuropeptides. Neuropeptides, 2010, 44(6), 457-466.
[http://dx.doi.org/10.1016/j.npep.2010.08.003] [PMID: 21047684]
[101]
Hook, V.; Funkelstein, L.; Wegrzyn, J.; Bark, S.; Kindy, M.; Hook, G. Cysteine Cathepsins in the secretory vesicle produce active peptides: Cathepsin L generates peptide neurotransmitters and cathepsin B produces beta-amyloid of Alzheimer’s disease. Biochim. Biophys. Acta, 2012, 1824(1), 89-104.
[http://dx.doi.org/10.1016/j.bbapap.2011.08.015] [PMID: 21925292]