Proteases of plasmodium falciparum as potential drug targets and inhibitors thereof

Current Topics in Medicinal Chemistry

Volumn 10, Issue 3, 2010, Pages 346-367

  Wegscheid Gerlach, Christof ^a   Gerber, Hans Dieter ^b   Diederich, Wibke E ^b  

^a BAYER PHARMA AG   (Germany)

^b PHILIPPS UNIVERSITY MARBURG   (Germany)

Author keywords

Falcipain; Malaria; Plasmepsin; Protease inhibitors

Indexed keywords

ACT 056822; ACT 057278; AMPRENAVIR; ASPARTIC PROTEINASE; ATAZANAVIR; CHLOROQUINE; CYSTEINE PROTEINASE; HEMOGLOBIN; INDINAVIR; JCP 104; JCP 405; KNI 10006; KNI 10538; KNI 727; LOPINAVIR; MRT 12113; NELFINAVIR; PEPSTATIN; PLASMEPSIN INHIBITOR; PRIMAQUINE; PROTEINASE INHIBITOR; PROTOZOAL PROTEIN; RITONAVIR; RO 404388; SAK1; SAQUINAVIR; UNCLASSIFIED DRUG; UNINDEXED DRUG; WR 268961; ZLI 044A; ZLI 48A;

ANTIMALARIAL ACTIVITY; DRUG INHIBITION; DRUG TARGETING; HUMAN; MALARIA; NONHUMAN; PLASMODIUM FALCIPARUM; PROTEIN FUNCTION; REVIEW; VALIDATION PROCESS;

CYSTEINE ENDOPEPTIDASES; CYSTEINE PROTEINASE INHIBITORS; DRUG DESIGN; MOLECULAR STRUCTURE; PLASMODIUM FALCIPARUM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 77949482144     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/156802610790725461     Document Type: Review

References (175)

1. Gardner, M. J.; Hall, N.; Fung, E.; White, O.; Berriman, M.; Hyman, R. W.; Carlton, J. M.; Pain, A.; Nelson, K. E.; Bowman, S.; Paulsen, I. T.; James, K.; Eisen, J. A.; Rutherford, K.; Salzberg, S. L.; Craig, A.; Kyes, S.; Chan, M.-S.; Nene, V.; Shallom, S. J.; Suh, B.; Peterson, J.; Angiuoli, S.; Pertea, M.; Allen, J.; Selengut, J.; Haft, D.; Mather, M. W.; Vaidya, A. B.; Martin, D. M. A.; Fairlamb, A. H.; Fraunholz, M. J.; Roos, D. S.; Ralph, S. A.; McFadden, G. I.; Cummings, L. M.; Subramanian, G. M.; Mungall, C.; Venter, J. C.; Carucci, D. J.; Hoffman, S. L.; Newbold, C.; Davis, R. W.; Fraser, C. M.; Barrell, B. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature, 2002, 419(6906), 498-511.
2. Florens, L.; Washburn, M. P.; Raine, J. D.; Anthony, R. M.; Grainger, M.; Haynes, J. D.; Moch, J. K.; Muster, N.; Sacci, J. B.; Tabb, D. L.; Witney, A. A.; Wolters, D.; Wu, Y.; Gardner, M. J.; Holder, A. A.; Sinden, R. E.; Yates, J. R.; Carucci, D. J. A proteomic view of the Plasmodium falciparum life cycle. Nature, 2002, 419(6906), 520-526.
3. Wu, Y.; Wang, X.; Liu, X.; Wang, Y. Data-mining approaches reveal hidden families of proteases in the genome of malaria parasite. Genome Res., 2003, 13, 601-616.
4. Wang, Y.; Wu, Y. Computer assisted searches for drug targets with emphasis on malarial proteases and their inhibitors. Curr. Drug Targets Infect. Disord., 2004, 4, 25-40.
5. Rawlings, N. D.; Morton, F. R.; Barrett, A. J. MEROPS: the peptidase database. Nucleic Acids Res., 2006, 34, D270-272.
6. Ginsburg, H. "Malaria Parasite Metabolic Pathways" http://sites.huji.ac.il/malaria/
7. Klemba, M.; Goldberg, D. E. Biological roles of proteases in parasitic protozoa. Annu. Rev. Biochem., 2002, 71(1), 275-305.
8. McKerrow, J. H.; Caffrey, C.; Kelly, B.; Loke, P. N.; Sajid, M. Proteases in parasitic diseases. Annu. Rev. Pathol. Mech. Dis., 2006, 1(1), 497-536.
9. Sharma, A. Malarial protease inhibitors: potential new chemotherapeutic agents. Curr. Opin. Investig. Drugs, 2007, 8(8), 642-652.
10. Blackman, M. J. Proteases involved in erythrocyte invasion by the malaria parasite function and potential as chemotherapeutic targets. Curr. Drug Targets, 2000, 1, 59-83.
11. Blackman, M. J. Proteases in host cell invasion by the malaria parasite. Cell. Microbiol., 2004, 6(10), 893-903.
12. Carruthers, V. B.; Blackman, M. J. A new release on life: emerging concepts in proteolysis and parasite invasion. Mol. Microbiol., 2005, 55(6), 1617-1630.
13. Iyer, J.; Grüner, A. C.; Rénia, L.; Snounou, G.; Preiser, P. R. Invasion of host cells by malaria parasites: a tale of two protein families. Mol. Microbiol., 2007, 65(2), 231-249.
14. Dowse, T.; Soldati, D. Host cell invasion by the apicomplexans: the significance of microneme protein proteolysis. Curr. Opin. Microbiol., 2004, 7(4), 388-396.
15. Withers-Martinez, C.; Jean, L.; Blackman, M. J. Subtilisin-like proteases of the malaria parasite. Mol. Microbiol., 2004, 53(1), 55-63.
16. Blackman, M. J. Malarial proteases and host cell egress: an 'emerging' cascade. Cell. Microbiol., 2008, 10(10), 1925-1934.
17. Salmon, B. L.; Oksman, A.; Goldberg, D. E. Malaria parasite exit from the host erythrocyte: A two-step process requiring extraerythrocytic proteolysis. Proc. Natl. Acad. Sci. USA, 2001, 98(1), 271-276.
18. Wickham, M. E.; Culvenor, J. G.; Cowman, A. F. Selective inhibition of a two-step egress of malaria parasites from the host erythrocyte. J. Biol. Chem., 2003, 278(39), 37658-37663.
19. Howell, S. A.; Well, I.; Fleck, S. L.; Kettleborough, C.; Collins, C. R.; Blackman, M. J. A single malaria merozoite serine protease mediates shedding of multiple surface proteins by juxtamembrane cleavage. J. Biol. Chem., 2003, 278(26), 23890-23898.
20. Uzureau, P.; Barale, J.-C.; Janse, C. J.; Waters, A. P.; Breton, C. B. Gene targeting demonstrates that the Plasmodium berghei subtilisin PbSUB2 is essential for red cell invasion and reveals spontaneous genetic recombination events. Cell. Microbiol., 2004, 6(1), 65-78.
21. Harris, P. K.; Yeoh, S.; Dluzewski, A. R.; O'Donnell, R. A.; Withers-Martinez, C.; Hackett, F.; Bannister, L. H.; Mitchell, G. H.; Blackman, M. J. Molecular identification of a malaria merozoite surface sheddase. PLoS Pathog., 2005, 1(3), 241-251.
22. Fleck, S. L.; Birdsall, B.; Babon, J.; Dluzewski, A. R.; Martin, S. R.; Morgan, W. D.; Angov, E.; Kettleborough, C. A.; Feeney, J.; Blackman, M. J.; Holder, A. A. Suramin and suramin analogues inhibit merozoite surface protein-1 secondary processing and erythrocyte invasion by the malaria parasite Plasmodium falciparum. J. Biol. Chem., 2003, 278(48), 47670-47677.
23. Yeoh, S.; O'Donnell, R. A.; Koussis, K.; Dluzewski, A. R.; Ansell, K. H.; Osborne, S. A.; Hackett, F.; Withers-Martinez, C.; Mitchell, G. H.; Bannister, L. H.; Bryans, J. S.; Kettleborough, C. A.; Blackman, M. J. Subcellular discharge of a serine protease mediates release of invasive malaria parasites from host erythrocytes. Cell, 2007, 131(6), 1072-1083.
24. Arastu-Kapur, S.; Ponder, E. L.; Fonovic, U. P.; Yeoh, S.; Yuan, F.; Fonovic, M.; Grainger, M.; Phillips, C. I.; Powers, J. C.; Bogyo, M. Identification of proteases that regulate erythrocyte rupture by the malaria parasite Plasmodium falciparum. Nat. Chem. Biol., 2008, 4(3), 203-213.
25. 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.
26. Dasaradhi, P. V. N.; Mohmmed, A.; Kumar, A.; Hossain, M. J.; Bhatnagar, R. K.; Chauhan, V. S.; Malhotra, P. A role of falcipain-2, principal cysteine proteases of Plasmodium falciparum in merozoite egression. Biochem. Biophys. Res. Commun., 2005, 336(4), 1062-1068.
27. Lew, V. L.; Tiffert, T.; Ginsburg, H. Excess hemoglobin digestion and the osmotic stability of Plasmodium falciparum-infected red blood cells. Blood, 2003, 101(10), 4189-4194.
28. Goldberg, D. E.; Slater, A. F.; Cerami, A.; Henderson, G. B. Hemoglobin degradation in the malaria parasite Plasmodium falciparum: an ordered process in a unique organelle. Proc. Natl. Acad. Sci. USA, 1990, 87(8), 2931-2935.
29. Francis, S. E.; Gluzman, I. Y.; Oksman, A.; Knickerbocker, A.; Mueller, R.; Bryant, M. L.; Sherman, D. R.; Russell, D. G.; Goldberg, D. E. Molecular characterization and inhibition of a Plasmodium falciparum aspartic hemoglobinase. EMBO J., 1994, 13(2), 306-317.
30. Rosenthal, P. J. Plasmodium falciparum: Effects of Proteinase Inhibitors on Globin Hydrolysis by Cultured Malaria Parasites. Exp. Parasitol., 1995, 80, (2), 272-281.
31. Goldberg, D. E.; Slater, A. F. G.; Beavis, R.; Chait, B.; Cerami, A.; Henderson, G. B. Hemoglobin degradation in the human malaria pathogen Plasmodium falciparum: a catabolic pathway initiated by a specific aspartic protease. J. Exp. Med., 1991, 173(4), 961-969.
32. Moon, R. P.; Tyas, L.; Certa, U.; Rupp, K.; Bur, D.; Jacquet, C.; Matile, H.; Loetscher, H.; Grueninger-Leitch, F.; Kay, J.; Dunn, B. M.; Berry, C.; Ridley, R. G. Expression and Characterisation of Plasmepsin I from Plasmodium falciparum. Eur. J. Biochem., 1997, 244(2), 552-560.
33. Gluzman, I. Y.; Francis, S. E.; Oksman, A.; Smith, C. E.; Duffin, K. L.; Goldberg, D. E. Order and specificity of the Plasmodium falciparum hemoglobin degradation pathway. J. Clin. Invest. 1994, 93(4), 1602-1608.
34. Dame, J. B.; Reddy, G. R.; Yowell, C. A.; Dunn, B. M.; Kay, J.; Berry, C. Sequence, expression and modeled structure of an aspartic proteinase from the human malaria parasite Plasmodium falciparum. Mol. Biochem. Parasitol., 1994, 64(2), 177-190.
35. Humphreys, M. J.; Moon, R. P.; Klinder, A.; Fowler, S. D.; Rupp, K.; Bur, D.; Ridley, R. G.; Berry, C. The aspartic proteinase from the rodent parasite Plasmodium berghei as a potential model for plasmepsins from the human malaria parasite, Plasmodium falciparum. FEBS Lett., 1999, 463(1-2), 43-48.
36. Banerjee, R.; Liu, J.; Beatty, W.; Pelosof, L.; Klemba, M.; Goldberg, D. E. Four plasmepsins are active in the Plasmodium falciparum food vacuole, including a protease with an active-site histidine. Proc. Natl. Acad. Sci. USA, 2002, 99(2), 990-995.
37. Shenai, B. R.; Sijwali, P. S.; Singh, A.; Rosenthal, P. J. Characterization of native and recombinant falcipain-2, a principal trophozoite cysteine protease and essential hemoglo-binase of Plasmodium falciparum. J. Biol. Chem., 2000, 275(37), 29000-29010.
38. Sijwali, P. S.; Rosenthal, P. J. Gene disruption confirms a critical role for the cysteine protease falcipain-2 in hemoglobin hydrolysis by Plasmodium falciparum. Proc. Natl. Acad. Sci. USA, 2004, 101(13), 4384-4389.
39. Hogg, T.; Nagarajan, K.; Herzberg, S.; Chen, L.; Shen, X.; Jiang, H.; Wecke, M.; Blohmke, C.; Hilgenfeld, R.; Schmidt, C. L. Structural and functional characterization of falcipain-2, a hemoglobinase from the malarial parasite Plasmodium falciparum. J. Biol. Chem., 2006, 281(35), 25425-25437.
40. Singh, N.; Sijwali, P. S.; Pandey, K. C.; Rosenthal, P. J. Plasmodium falciparum: Biochemical characterization of the cysteine protease falcipain-2'. Exp. Parasitol., 2006, 112(3), 187-192.
41. Jeong, J.-J.; Kumar, A.; Hanada, T.; Seo, P.-S.; Li, X.; Hanspal, M.; Chishti, A. H. Cloning and characterization of Plasmodium falciparum cysteine protease, falcipain-2B. Blood Cells Mol. Dis., 2006, 36(3), 429-435.
42. Sijwali, P. S.; Shenai, B. R.; Gut, J.; Singh, A.; Rosenthal, P. J. Expression and characterization of the Plasmodium falciparum haemoglobinase falcipain-3. Biochem. J., 2001, 360 (Pt 2), 481-489.
43. Eggleson, K. K.; Duffin, K. L.; Goldberg, D. E. Identification and characterization of falcilysin, a metallopeptidase involved in hemoglobin catabolism within the malaria parasite Plasmodium falciparum. J. Biol. Chem., 1999, 274(45), 32411-32417.
44. Klemba, M.; Gluzman, I.; Goldberg, D. E. A Plasmodium falciparum dipeptidyl aminopeptidase i participates in vacuolar hemoglobin degradation. J. Biol. Chem., 2004, 279(41), 43000-43007.
45. Coombs, G. H.; Goldberg, D. E.; Klemba, M.; Berry, C.; Kay, J.; Mottram, J. C. Aspartic proteases of Plasmodium falciparum and other parasitic protozoa as drug targets. Trends Parasitol., 2001, 17(11), 532-537.
46. Semenov, A.; Olson, J. E.; Rosenthal, P. J. Antimalarial synergy of cysteine and aspartic protease inhibitors. Antimicrob. Agents Chemother., 1998, 42(9), 2254-2258.
47. Klemba, M.; Goldberg, D. E. Characterization of plasmepsin V, a membrane-bound aspartic protease homolog in the endoplasmic reticulum of Plasmodium falciparum. Mol. Biochem. Parasitol., 2005, 143(2), 183-191.
48. Bonilla, J. A.; Bonilla, T. D.; Yowell, C. A.; Fujioka, H.; Dame, J. B. Critical roles for the digestive vacuole plasmepsins of Plasmodium falciparum in vacuolar function. Mol. Microbiol., 2007, 65(1), 64-75.
49. Dame, J. B.; Yowell, C. A.; Omara-Opyene, L.; Carlton, J. M.; Cooper, R. A.; Li, T. Plasmepsin 4, the food vacuole aspartic proteinase found in all Plasmodium spp. infecting man. Mol. Biochem. Parasitol., 2003, 130(1), 1-12.
50. Boss, C.; Richard-Bildstein, S.; Weller, T.; Fischli, W.; Meyer, S.; Binkert, C. Inhibitors of the Plasmodium falciparum parasite aspartic protease plasmepsin II as potential antimalarial agents. Curr. Med. Chem., 2003, 10(11), 883-907.
51. Boss, C.; Corminboeuf, O.; Grisostomi, C.; Meyer, S.; Jones, A. F.; Prade, L.; Binkert, C.; Fischli, W.; Weller, T.; Bur, D. Achiral, cheap, and potent inhibitors of plasmepsins I, II, and IV. ChemMedChem, 2006, 1(12), 1341-1345.
52. Binkert, C.; Frigerio, M.; Jones, A.; Meyer, S.; Pesenti, C.; Prade, L.; Viani, F.; Zanda, M. Replacement of isobutyl by trifluoromethyl in pepstatin a selectively affects inhibition of aspartic proteinases. ChemBioChem, 2006, 7(1), 181-186.
53. Ersmark, K.; Samuelsson, B.; Hallberg, A. Plasmepsins as potential targets for new antimalarial therapy. Med. Res. Rev., 2006, 26(5), 626-666.
54. Mungthin, M.; Bray, P. G.; Ridley, R. G.; Ward, S. A. Central role of hemoglobin degradation in mechanisms of action of 4-aminoquinolines, quinoline methanols, and phenanthrene methanols. Antimicrob. Agents Chemother., 1998, 42(11), 2973-2977.
55. Wyatt, D. M.; Berry, C. Activity and inhibition of plasmepsin IV, a new aspartic proteinase from the malaria parasite, Plasmodium falciparum. FEBS Lett., 2002, 513(2-3), 159-162.
56. Tyas, L.; Gluzman, I.; Moon, R. P.; Rupp, K.; Westling, J.; Ridley, R. G.; Kay, J.; Goldberg, D. E.; Berry, C. Naturally-occurring and recombinant forms of the aspartic proteinases plasmepsins I and II from the human malaria parasite Plasmodium falciparum. FEBS Lett., 1999, 454(3), 210-214.
57. Oefner, C.; Binggeli, A.; Breu, V.; Bur, D.; Clozel, J. P.; D'Arcy, A.; Dorn, A.; Fischli, W.; Grüninger, F.; Güller, R.; Hirth, G.; Märki, H. P.; Mathews, S.; Müller, M.; Ridley, R. G.; Stadler, H.; Vieira, E.; Wilhelm, M.; Winkler, F. K.; Wostl, W. Renin inhibition by substituted piperidines: A novel paradigm for the inhibition of monomeric aspartic proteinases? Chem. Biol., 1999, 6(3), 127-131.
58. Boss, C.; Corminboeuf, O.; Grisostomi, C.; Weller, T. Inhibitors of aspartic proteases - potential antimalarial agents. Expert Opin. Ther. Pat., 2006, 16(3), 295-317.
59. Mueller, R.; Huerzeler, M.; Boss, C. Synthesis of plasmepsin II inhibitors - potential antimalarial agents. Molecules, 2003, 8, 556-564.
60. Corminboeuf, O.; Dunet, G.; Hafsi, M.; Grimont, J.; Grisostomi, C.; Meyer, S.; Binkert, C.; Bur, D.; Jones, A.; Prade, L.; Brun, R.; Boss, C. Inhibitors of Plasmepsin II-potential antimalarial agents. Bioorg. Med. Chem. Lett., 2006, 16(24), 6194-6199.
61. Prade, L.; Jones, A. F.; Boss, C.; Richard-Bildstein, S.; Meyer, S.; Binkert, C.; Bur, D. X-ray structure of plasmepsin II complexed with a potent achiral inhibitor. J. Biol. Chem., 2005, 280(25), 23837-23843.
62. Haque, T. S.; Skillman, A. G.; Lee, C. E.; Habashita, H.; Gluzman, I. Y.; Ewing, T. J.; Goldberg, D. E.; Kuntz, I. D.; Ellman, J. A. Potent, low-molecular-weight non-peptide inhibitors of malarial aspartyl protease plasmepsin II. J. Med. Chem., 1999, 42(8), 1428-1440.
63. Brinner, K. M.; Mi Kim, J.; Habashita, H.; Gluzman, I. Y.; Goldberg, D. E.; Ellman, J. A. Novel and potent anti-malarial agents. Bioorg. Med. Chem., 2002, 10(11), 3649-3661.
64. Choi, C. Y. H.; Schneider, E. L.; Kim, J. M.; Gluzman, I. Y.; Goldberg, D. E.; Ellman, J. A.; Marletta, M. A. Interference with heme binding to histidine-rich protein-2 as an antimalarial strategy. Chem. Biol., 2002, 9(8), 881-889.
65. Brinner, K. M.; Powles, M. A.; Schmatz, D. M.; Ellman, J. A. Potent 4-aminopiperidine based antimalarial agents. Bioorg. Med. Chem. Lett., 2005, 15(2), 345-348.
66. Nezami, A.; Luque, I.; Kimura, T.; Kiso, Y.; Freire, E. Identification and characterization of allophenylnorstatine-based inhibitors of plasmepsin II, an antimalarial target. Biochemistry, 2002, 41(7), 2273-2280.
67. Madabushi, A.; Chakraborty, S.; Fisher, S. Z.; Clemente, J. C.; Yowell, C.; Agbandje-McKenna, M.; Dame, J. B.; Dunn, B. M.; McKenna, R. Crystallization and preliminary X-ray analysis of the aspartic protease plasmepsin 4 from the malarial parasite Plasmodium malariae. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun., 2005, 61(Pt 2), 228-231.
68. Clemente, J. C.; Govindasamy, L.; Madabushi, A.; Fisher, S. Z.; Moose, R. E.; Yowell, C. A.; Hidaka, K.; Kimura, T.; Hayashi, Y.; Kiso, Y.; Agbandje-McKenna, M.; Dame, J. B.; Dunn, B. M.; McKenna, R. Structure of the aspartic protease plasmepsin 4 from the malarial parasite Plasmodium malariae bound to an allophenylnorstatine-based inhibitor. Acta Crystallogr. Sect D: Biol. Crystallogr., 2006, 62(Pt 3), 246-252.
69. Kiso, A.; Hidaka, K.; Kimura, T.; Hayashi, Y.; Nezami, A.; Freire, E.; Kiso, Y. Search for substrate-based inhibitors fitting the S2' space of malarial aspartic protease plasmepsin II. J. Pept. Sci., 2004, 10(11), 641-647.
70. Hidaka, K.; Kimura, T.; Tsuchiya, Y.; Kamiya, M.; Ruben, A. J.; Freire, E.; Hayashi, Y.; Kiso, Y. Additional interaction of allophenylnorstatine- containing tripeptidomimetics with malarial aspartic protease plasmepsin II. Bioorg. Med. Chem. Lett., 2007, 17(11), 3048-3052.
71. Hidaka, K.; Kimura, T.; Ruben, A. J.; Uemura, T.; Kamiya, M.; Kiso, A.; Okamoto, T.; Tsuchiya, Y.; Hayashi, Y.; Freire, E.; Kiso, Y. Antimalarial activity enhancement in hydroxymethylcarbonyl (HMC) isostere-based dipeptidomimetics targeting malarial aspartic protease plasmepsin. Bioorg. Med. Chem., 2008, 16(23), 10049-10060.
72. Romeo, S.; Dell'Agli, M.; Parapini, S.; Rizzi, L.; Galli, G.; Mondani, M.; Sparatore, A.; Taramelli, D.; Bosisio, E. Plasmepsin II inhibition and antiplasmodial activity of Primaquine-Statine 'double-drugs'. Bioorg. Med. Chem. Lett., 2004, 14(11), 2931-2934.
73. Dell'Agli, M.; Parapini, S.; Galli, G.; Vaiana, N.; Taramelli, D.; Sparatore, A.; Liu, P.; Dunn, B. M.; Bosisio, E.; Romeo, S. High antiplasmodial activity of novel plasmepsins I and II inhibitors. J. Med. Chem., 2006, 49(25), 7440-7449.
74. Jiang, S.; Prigge, S. T.; Wei, L.; Gao, Y.; Hudson, T. H.; Gerena, L.; Dame, J. B.; Kyle, D. E. New class of small nonpeptidyl compounds blocks Plasmodium falciparum development In vitro by inhibiting plasmepsins. Antimicrob. Agents Chemother., 2001, 45(9), 2577-2584.
75. Bhattacharya, G.; Gerena, L.; Jiang, S.; Werbovetz, K. A. Activity of amidine-containing diphenylureas against P. falciparum. Lett. Drug Des. Discov., 2005, 2, 162-164.
76. Stead, A. M. W.; Bray, P. G.; Edwards, I. G.; DeKoning, H. P.; Elford, B. C.; Stocks, P. A.; Ward, S. A. Diamidine compounds: selective uptake and targeting in plasmodium falciparum. Mol. Pharmacol., 2001, 59(5), 1298-1306.
77. Ismail, M. A.; Brun, R.; Easterbrook, J. D.; Tanious, F. A.; Wilson, W. D.; Boykin, D. W. Synthesis and antiprotozoal activity of Azaanalogues of furamidine. J. Med. Chem., 2003, 46(22), 4761-4769.
78. Skinner-Adams, T. S.; McCarthy, J. S.; Gardiner, Donald L.; Hilton, Petrina M.; Andrews, Katherine T. Antiretrovirals as antimalarial agents. J. Infect. Dis., 2004, 190(11), 1998-2000.
79. Parikh, S.; Gut, J.; Istvan, E.; Goldberg, D. E.; Havlir, D. V.; Rosenthal, P. J. Antimalarial activity of human immunodeficiency virus type 1 protease inhibitors. Antimicrob. Agents Chemother., 2005, 49(7), 2983-2985.
80. Andrews, K. T.; Fairlie, D. P.; Madala, P. K.; Ray, J.; Wyatt, D. M.; Hilton, P. M.; Melville, L. A.; Beattie, L.; Gardiner, D. L.; Reid, R. C.; Stoermer, M. J.; Skinner-Adams, T.; Berry, C.; McCarthy, J. S. Potencies of human immunodeficiency virus protease inhibitors In vitro against Plasmodium falciparum and in vivo against murine malaria. Antimicrob. Agents Chemother., 2006, 50(2), 639-648.
81. Parikh, S.; Liu, J.; Sijwali, P.; Gut, J.; Goldberg, D. E.; Rosenthal, P. J. Antimalarial effects of human immunodeficiency virus type 1 protease inhibitors differ from those of the aspartic protease inhibitor pepstatin. Antimicrob. Agents Chemother., 2006, 50(6), 2207-2209.
82. Skinner-Adams, T. S.; Andrews, K. T.; Melville, L.; McCarthy, J.; Gardiner, D. L. Synergistic interactions of the antiretroviral protease inhibitors saquinavir and ritonavir with chloroquine and mefloquine against plasmodium falciparum in vitro. Antimicrob. Agents Chemother., 2007, 51(2), 759-762.
83. He, Z.; Qin, L.; Chen, L.; Peng, N.; You, J.; Chen, X. Synergy of Human Immunodeficiency Virus Protease Inhibitors with Chloroquine against Plasmodium falciparum in vitro and Plasmodium chabaudi in vivo. Antimicrob. Agents Chemother., 2008, 52(7), 2653-2656.
84. Lek-Uthai, U.; Suwanarusk, R.; Ruengweerayut, R.; Skinner-Adams, T. S.; Nosten, F.; Gardiner, D. L.; Boonma, P.; Piera, K. A.; Andrews, K. T.; MacHunter, B.; McCarthy, J. S.; Anstey, N. M.; Price, R. N.; Russell, B. Stronger activity of human immunodeficiency virus type 1 protease inhibitors against clinical isolates of Plasmodium vivax than against those of P. falciparum. Antimicrob. Agents Chemother., 2008, 52(7), 2435-2441.
85. Hobbs, Charlotte V.; Voza, T.; Coppi, A.; Kirmse, B.; Marsh, K.; Borkowsky, W.; Sinnis, P. HIV protease inhibitors inhibit the development of preerythrocytic-stage plasmodium parasites. J. Infect. Dis., 2009, 199(1), 134-141.
86. Rosenthal, P. J.; Sijwali, P. S.; Singh, A.; Shenai, B. R. Cysteine proteases of malaria parasites: targets for chemotherapy. Curr. Pharm. Des., 2002, 8(18), 1659-1672.
87. Rosenthal, P. J. Cysteine proteases of malaria parasites. Int. J. Parasitol., 2004, 34(13-14), 1489-1499.
88. Shenai, B. R.; Semenov, A. V.; Rosenthal, P. J. Stage-Specific antimalarial activity of cysteine protease inhibitors. Biol. Chem., 2002, 383(5), 843-847.
89. Rosenthal, P. J.; McKerrow, J. H.; Aikawa, M.; Nagasawa, H.; Leech, J. H. A malarial cysteine proteinase is necessary for hemoglobin degradation by Plasmodium falciparum. J. Clin. Invest., 1988, 82(5), 1560-1566.
90. 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.
91. Wang, S. X.; Pandey, K. C.; Somoza, J. R.; Sijwali, P. S.; Kortemme, T.; Brinen, L. S.; Fletterick, R. J.; Rosenthal, P. J.; McKerrow, J. H. Structural basis for unique mechanisms of folding and hemoglobin binding by a malarial protease. Proc. Natl. Acad. Sci. USA, 2006, 103(31), 11503-11508.
92. 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.
93. Dua, M.; Raphael, P.; Sijwali, P. S.; Rosenthal, P. J.; Hanspal, M. Recombinant falcipain-2 cleaves erythrocyte membrane ankyrin and protein 4.1. Mol. Biochem. Parasitol., 2001, 116(1), 95-99.
94. 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.
95. Drew, M. E.; Banerjee, R.; Uffman, E. W.; Gilbertson, S.; Rosenthal, P. J.; Goldberg, D. E. Plasmodium food vacuole Plasmepsins are activated by Falcipains. J. Biol. Chem., 2008, 283(19), 12870-12876.
96. Sijwali, P. S.; Koo, J.; Singh, N.; Rosenthal, P. J. Gene disruptions demonstrate independent roles for the four falcipain cysteine proteases of Plasmodium falciparum. Mol. Biochem. Parasitol., 2006, 150(1), 96-106.
97. Sijwali, P. S.; Kato, K.; Seydel, K. B.; Gut, J.; Lehman, J.; Klemba, M.; Goldberg, D. E.; Miller, L. H.; Rosenthal, P. J. Plasmodium falciparum cysteine protease falcipain-1 is not essential in erythrocytic stage malaria parasites. Proc. Natl. Acad. Sci. USA, 2004, 101(23), 8721-8726.
98. Eksi, S.; Czesny, B.; Greenbaum, D. C.; Bogyo, M.; Williamson, K. C. Targeted disruption of Plasmodium falciparum cysteine protease, falcipain 1, reduces oocyst production, not erythrocytic stage growth. Mol. Microbiol., 2004, 53(1), 243-250.
99. Eksi, S.; Czesny, B.; van Gemert, G. J.; Sauerwein, R. W.; Eling, W.; Williamson, K. C. Inhibition of plasmodium falciparum oocyst production by membrane-permeant cysteine protease inhibitor E64d. Antimicrob. Agents Chemother., 2007, 51(3), 1064-1070.
100. Chan, C.; Goh, L. L.; Sim, T. S. Differences in biochemical properties of the Plasmodial falcipain-2 and berghepain-2 orthologues: implications for In vivo screens of inhibitors. FEMS Microbiol. Lett., 2005, 249(2), 315-321.
101. Ramjee, M. K.; Flinn, N. S.; Pemberton, T. P.; Quibell, M.; Wang, Y.; Watts, J. P. Substrate mapping and inhibitor profiling of falcipain-2, falcipain-3 and berghepain-2: implications for peptidase anti-malarial drug discovery. Biochem. J., 2006, 399(1), 47-57.
102. Lee, B. J.; Singh, A.; Chiang, P.; Kemp, S. J.; Goldman, E. A.; Weinhouse, M. I.; Vlasuk, G. P.; Rosenthal, P. J. Antimalarial activities of novel synthetic cysteine protease inhibitors. Antimicrob. Agents Chemother., 2003, 47(12), 3810-3814.
103. Pandey, K. C.; Singh, N.; Arastu-Kapur, S.; Bogyo, M.; Rosenthal, P. J. Falstatin, a cysteine protease inhibitor of Plasmodium falciparum, facilitates erythrocyte invasion. PLoS Pathog., 2006, 2(11), e117.
104. Palmer, J. T.; Rasnick, D.; Klaus, J. L.; Bromme, D. Vinyl sulfones as Mechanism-Based cysteine protease inhibitors. J. Med. Chem., 1995, 38(17), 3193-3196.
105. 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.
106. 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.
107. 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.
108. Valente, C.; Guedes, R. C.; Moreira, R.; Iley, J.; Gut, J.; Rosenthal, P. J. Dipeptide vinyl sultams: synthesis via the Wittig-Horner reaction and activity against papain, falcipain-2 and Plasmodium falciparum. Bioorg. Med. Chem. Lett., 2006, 16(15), 4115-4119.
109. Zhu, S.; Hudson, T. H.; Kyle, D. E.; Lin, A. J. Synthesis and in vitro studies of novel pyrimidinyl peptidomimetics as potential antimalarial therapeutic agents. J. Med. Chem., 2002, 45(16), 3491-3496.
110. Verissimo, E.; Berry, N.; Gibbons, P.; Cristiano, M. L.; Rosenthal, P. J.; Gut, J.; Ward, S. A.; O'Neill, P. M. Design and synthesis of novel 2-pyridone peptidomimetic falcipain 2/3 inhibitors. Bioorg. Med. Chem. Lett., 2008, 18(14), 4210-4214.
111. Scheidt, K. A.; Roush, W. R.; McKerrow, J. H.; Selzer, P. M.; Hansell, E.; Rosenthal, P. J. Structure-based design, synthesis and evaluation of conformationally constrained cysteine protease inhibitors. Bioorg. Med. Chem., 1998, 6(12), 2477-2494.
112. Micale, N.; Kozikowski, A. P.; Ettari, R.; Grasso, S.; Zappala, M.; Jeong, J.-J.; Kumar, A.; Hanspal, M.; Chishti, A. H. Novel peptidomimetic cysteine protease inhibitors as potential antimalarial agents. J. Med. Chem., 2006, 49(11), 3064-3067.
113. Ettari, R.; Nizi, E.; Di Francesco, M. E.; Dude, M. A.; Pradel, G.; Vicik, R.; Schirmeister, T.; Micale, N.; Grasso, S.; Zappala, M. Development of peptidomimetics with a vinyl sulfone warhead as irreversible falcipain-2 inhibitors. J. Med. Chem., 2008, 51(4), 988-996.
114. Ettari, R.; Nizi, E.; Di Francesco, M. E.; Micale, N.; Grasso, S.; Zappala, M.; Vicik, R.; Schirmeister, T. Nonpeptidic vinyl and allyl phosphonates as falcipain-2 inhibitors. ChemMedChem, 2008, 3(7), 1030-1033.
115. Chen, M.; Theander, T. G.; Christensen, S. B.; Hviid, L.; Zhai, L.; Kharazmi, A. Licochalcone A, a new antimalarial agent, inhibits in vitro growth of the human malaria parasite Plasmodium falciparum and protects mice from P. yoelii infection. Antimicrob. Agents Chemother, 1994, 38(7), 1470-1475.
116. Chen, M.; Brøgger Christensen, S.; Zhai, L.; Rasmussen, M. H.; Theander, T. G.; Frøkjaer, S.; Steffansen, B.; Davidsen, J.; Kharazmi, A. The Novel Oxygenated Chalcone, 2,4-Dimethoxy-4'-Butoxychalcone, Exhibits potent activity against human malaria parasite plasmodium falciparum in vitro and rodent parasites plasmodium berghei and plasmodium yoelii In Vivo. J. Infect. Dis., 1997, 176(5), 1327-1333.
117. Li, Z.; Chen, X.; Davidson, E.; Zwang, O.; Mendis, C.; Ring, C. S.; Roush, W. R.; Fegley, G.; Li, R.; Rosenthal, P. J.; Lee, G. K.; Kenyon, G. L.; Kuntz, I. D.; Cohen, F. E. Anti-malarial drug development using models of enzyme structure. Chem. Biol., 1994, 1(1), 31-37.
118. Li, R.; Chen, X.; Gong, B.; Dominguez, J. N.; Davidson, E.; Kurzban, G.; Miller, R. E.; Nuzum, E. O.; Rosenthal, P. J. In Vitro antimalarial activity of chalcones and their derivatives. J. Med. Chem., 1995, 38(26), 5031-5037.
119. Li, R.; Chen, X.; Gong, B.; Selzer, P. M.; Li, Z.; Davidson, E.; Kurzban, G.; Miller, R. E.; Nuzum, E. O.; McKerrow, J. H.; Fletterick, R. J.; Gillmor, S. A.; Craik, C. S.; Kuntz, I. D.; Cohen, F. E.; Kenyon, G. L. Structure-based design of parasitic protease inhibitors. Bioorg. Med. Chem., 1996, 4(9), 1421-1427.
120. Gutteridge, C. E.; Nichols, D. A.; Curtis, S. M.; Thota, D. S.; Vo, J. V.; Gerena, L.; Montip, G.; Asher, C. O.; Diaz, D. S.; DiTusa, C. A.; Smith, K. S.; Bhattacharjee, A. K. In vitro and in vivo efficacy and in vitro metabolism of 1-phenyl-3-aryl-2-propen-1-ones against Plasmodium falciparum. Bioorg. Med. Chem. Lett., 2006, 16(21), 5682-5686.
121. Liu, M.; Wilairat, P.; Go, M.-L. Antimalarial alkoxylated and hydroxylated chalones: structure-activity relationship analysis. J. Med. Chem., 2001, 44(25), 4443-4452.
122. Dominguez, J. N.; Charris, J. E.; Lobo, G.; Gamboa de Dominguez, N.; Moreno, M. M.; Riggione, F.; Sanchez, E.; Olson, J.; Rosenthal, P. J. Synthesis of quinolinyl chalcones and evaluation of their antimalarial activity. Eur. J. Med. Chem., 2001, 36(6), 555-560.
123. Dominguez, J. N.; Leon, C.; Rodrigues, J.; Gamboa de Dominguez, N.; Gut, J.; Rosenthal, P. J. Synthesis and evaluation of new antimalarial phenylurenyl chalcone derivatives. J. Med. Chem., 2005, 48(10), 3654-3658.
124. Desai, P. V.; Patny, A.; Sabnis, Y.; Tekwani, B.; Gut, J.; Rosenthal, P.; Srivastava, A.; Avery, M. Identification of novel parasitic cysteine protease inhibitors using virtual screening. 1. The ChemBridge database. J. Med. Chem., 2004, 47(26), 6609-6615.
125. Desai, P. V.; Patny, A.; Gut, J.; Rosenthal, P. J.; Tekwani, B.; Srivastava, A.; Avery, M. Identification of novel parasitic cysteine protease inhibitors by use of virtual screening. 2. The available chemical directory. J. Med. Chem., 2006, 49(5), 1576-1584.
126. 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.
127. 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.
128. Fujii, N.; Mallari, J. P.; Hansell, E. J.; Mackey, Z.; Doyle, P.; Zhou, Y. M.; Gut, J.; Rosenthal, P. J.; McKerrow, J. H.; Guy, R. K. Discovery of potent thiosemicarbazone inhibitors of rhodesain and cruzain. Bioorg. Med. Chem. Lett., 2005, 15(1), 121-123.
129. Chiyanzu, I.; Hansell, E.; Gut, J.; Rosenthal, P. J.; McKerrow, J. H.; Chibale, K. Synthesis and evaluation of isatins and thiosemicarbazone derivatives against cruzain, falcipain-2 and rhodesain. Bioorg. Med. Chem. Lett., 2003, 13(20), 3527-3530.
130. Chiyanzu, I.; Clarkson, C.; Smith, P. J.; Lehman, J.; Gut, J.; Rosenthal, P. J.; Chibale, K. Design, synthesis and anti-plasmodial evaluation in vitro of new 4-aminoquinoline isatin derivatives. Bioorg. Med. Chem., 2005, 13(9), 3249-3261.
131. Biot, C.; Pradines, B.; Sergeant, M.-H.; Gut, J.; Rosenthal, P. J.; Chibale, K. Design, synthesis, and antimalarial activity of structural chimeras of thiosemicarbazone and ferroquine analogues. Bioorg. Med. Chem. Lett., 2007, 17(23), 6434-6438.
132. Chipeleme, A.; Gut, J.; Rosenthal, P. J.; Chibale, K. Synthesis and biological evaluation of phenolic Mannich bases of benzaldehyde and (thio)semicarbazone derivatives against the cysteine protease falcipain-2 and a chloroquine resistant strain of Plasmodium falciparum. Bioorg. Med. Chem., 2007, 15(1), 273-282.
133. Schirmeister, T.; Klockow, A. Cysteine protease inhibitors containing small rings. Mini Rev. Med. Chem., 2003, 3(6), 585-596.
134. Gelhaus, C.; Vicik, R.; Hilgenfeld, R.; Schmidt, C. L.; Leippe, M.; Schirmeister, T. Synthesis and antiplasmodial activity of a cysteine protease-inhibiting biotinylated aziridine-2,3-dicarboxylate. Biol. Chem., 2004, 385(5), 435-438.
135. Schulz, F.; Gelhaus, C.; Degel, B.; Vicik, R.; Heppner, S.; Breuning, A.; Leippe, M.; Gut, J.; Rosenthal, Philip J.; Schirmeister, T. Screening of protease inhibitors as antiplasmodial agents. Part I: Aziridines and epoxides. ChemMedChem, 2007, 2(8), 1214-1224.
136. Li, X.; Chen, H.; Jeong, J. J.; Chishti, A. H. BDA-410: a novel synthetic calpain inhibitor active against blood stage malaria. Mol. Biochem. Parasitol., 2007, 155(1), 26-32.
137. Dude, M. A.; Kaeppler, U.; Herb, M.; Schiller, M.; Schulz, F.; Vedder, B.; Heppner, S.; Pradel, G.; Gut, J.; Rosenthal, P. J.; Schirmeister, T.; Leippe, M.; Gelhaus, C. Synthesis and evaluation of non-peptidic cysteine protease inhibitors of P. falciparum derived from etacrynic acid. Molecules, 2009, 14(1), 19-35.
138. Murata, C. E.; Goldberg, D. E. Plasmodium falciparum falcilysin: a metalloprotease with dual specificity. J. Biol. Chem., 2003, 278(39), 38022-38028.
139. Murata, C. E.; Goldberg, D. E. Plasmodium falciparum falcilysin: an unprocessed food vacuole enzyme. Mol. Biochem. Parasitol., 2003, 129(1), 123-126.
140. Ponpuak, M.; Klemba, M.; Park, M.; Gluzman, I. Y.; Lamppa, G. K.;
141. Dalal, S.; Klemba, M. Roles for Two Aminopeptidases in Vacuolar Hemoglobin Catabolism in Plasmodium falciparum. J. Biol. Chem., 2007, 282(49), 35978-35987.
142. Cunningham, E.; Drag, M.; Kafarski, P.; Bell, A. Chemical target validation studies of aminopeptidase in malaria parasites using alpha-aminoalkylphosphonate and phosphonopeptide inhibitors. Antimicrob. Agents Chemother., 2008, 52(9), 3221-3228.
143. Nankya-Kitaka, M. F.; Curley, G. P.; Gavigan, C. S.; Bell, A.; Dalton, J. P. Plasmodium chabaudi chabaudi and P. falciparum: inhibition of aminopeptidase and parasite growth by bestatin and nitrobestatin. Parasitol. Res., 1998, 84(7), 552-558.
144. Gavigan, C. S.; Dalton, J. P.; Bell, A. The role of aminopeptidases in haemoglobin degradation in Plasmodium falciparum-infected erythrocytes. Mol. Biochem. Parasitol., 2001, 117(1), 37-48.
145. Gavigan, C. S.; Machado, S. G.; Dalton, J. P.; Bell, A. Analysis of antimalarial synergy between bestatin and endoprotease inhibitors using statistical response-surface modelling. Antimicrob. Agents Chemother., 2001, 45(11), 3175-3181.
146. Allary, M.; Schrevel, J.; Florent, I. Properties, stage-dependent expression and localization of Plasmodium falciparum M1 family zinc-aminopeptidase. Parasitology, 2002, 125(Pt 1), 1-10.
147. Grembecka, J.; Mucha, A.; Cierpicki, T.; Kafarski, P. The most potent organophosphorus inhibitors of leucine aminopeptidase. Structure-based design, chemistry, and activity. J. Med. Chem., 2003, 46(13), 2641-2655.
148. McGowan, S.; Porter, C. J.; Lowther, J.; Stack, C. M.; Golding, S. J.; Skinner-Adams, T. S.; Trenholme, K. R.; Teuscher, F.; Donnelly, S. M.; Grembecka, J.; Mucha, A.; Kafarski, P.; Degori, R.; Buckle, A. M.; Gardiner, D. L.; Whisstock, J. C.; Dalton, J. P. Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase. Proc. Natl. Acad. Sci. USA, 2009, 106(8), 2537-2542.
149. Gerlach, C.; Münzel, M.; Baum, B.; Gerber, H. D.; Craan, T.; Diederich, W. E.; Klebe, G. KNOBLE: a knowledge-based approach for the design and synthesis of readily accessible small-molecule chemical probes to test protein binding. Angew. Chem. Int. Ed., 2007, 46(47), 9105-9109.
150. Flipo, M.; Florent, I.; Grellier, P.; Sergheraert, C.; Deprez-Poulain, R. Design, synthesis and antimalarial activity of novel, quinoline-based, zinc metallo-aminopeptidase inhibitors. Bioorg. Med. Chem. Lett., 2003, 13(16), 2659-2662.
151. Flipo, M.; Beghyn, T.; Leroux, V.; Florent, I.; Deprez, B. P.; Deprez-Poulain, R. F. Novel selective inhibitors of the zinc plasmodial aminopeptidase PfA-M1 as potential antimalarial agents. J. Med. Chem., 2007, 50(6), 1322-1334.
152. Deprez-Poulain, R.; Melnyk, P. 1,4-bis(3-aminopropyl)piperazine libraries: from the discovery of classical chloroquine-like antimalarials to the identification of new targets. Comb. Chem. High Throughput Screen. 2005, 8, 39-48.
153. Gardiner, D. L.; Trenholme, K. R.; Skinner-Adams, T. S.; Stack, C. M.; Dalton, J. P. Overexpression of leucyl aminopeptidase in Plasmodium falciparum parasites. Target for the antimalarial activity of bestatin. J. Biol. Chem., 2006, 281(3), 1741-1745.
154. Stack, C. M.; Lowther, J.; Cunningham, E.; Donnelly, S.; Gardiner, D. L.; Trenholme, K. R.; Skinner-Adams, T. S.; Teuscher, F.; Grembecka, J.; Mucha, A.; Kafarski, P.; Lua, L.; Bell, A.; Dalton, J. P. Characterization of the Plasmodium falciparum M17 leucyl aminopeptidase. A protease involved in amino acid regulation with potential for antimalarial drug development. J. Biol. Chem., 2007, 282(3), 2069-2080.
155. Skinner-Adams, T. S.; Lowther, J.; Teuscher, F.; Stack, C. M.; Grembecka, J.; Mucha, A.; Kafarski, P.; Trenholme, K. R.; Dalton, J. P.; Gardiner, D. L. Identification of phosphinate dipeptide analog inhibitors directed against the Plasmodium falciparum M17 leucine aminopeptidase as lead antimalarial compounds. J. Med. Chem., 2007, 50(24), 6024-6031.
156. Mucha, A.; Lämmerhofer, M.; Lindner, W.; Pawelczak, M.; Kafarski, P. Individual stereoisomers of phosphinic dipeptide inhibitor of leucine aminopeptidase. Bioorg. Med. Chem. Lett., 2008, 18(5), 1550-1554.
157. Teuscher, F.; Lowther, J.; Skinner-Adams, T. S.; Spielmann, T.; Dixon, M. W.; Stack, C. M.; Donnelly, S.; Mucha, A.; Kafarski, P.; Vassiliou, S.; Gardiner, D. L.; Dalton, J. P.; Trenholme, K. R. The M18 aspartyl aminopeptidase of the human malaria parasite Plasmodium falciparum. J. Biol. Chem., 2007, 282(42), 30817-30826.
158. Lauterbach, S. B.; Coetzer, T. L. The M18 aspartyl aminopeptidase of Plasmodium falciparum binds to human erythrocyte spectrin In vitro. Malar. J., 2008, 7, 161.
159. Zhang, P.; Nicholson, D. E.; Bujnicki, J. M.; Su, X.; Brendle, J. J.; Ferdig, M.; Kyle, D. E.; Milhous, W. K.; Chiang, P. K. Angiogenesis inhibitors specific for methionine aminopeptidase 2 as drugs for malaria and leishmaniasis. J. Biomed. Sci., 2002, 9(1), 34-40.
160. Chen, X.; Xie, S.; Bhat, S.; Kumar, N.; Shapiro, T. A.; Liu, J. O. Fumagillin and fumarranol interact with P. falciparum methionine aminopeptidase 2 and inhibit malaria parasite growth In vitro and In vivo. Chem. Biol., 2009, 16(2), 193-202.
161. Chen, X.; Chong, C. R.; Shi, L.; Yoshimoto, T.; Sullivan, D. J. Jr.; Liu, J. O. Inhibitors of Plasmodium falciparum methionine aminopeptidase 1b possess antimalarial activity. Proc. Natl. Acad. Sci. USA, 2006, 103(39), 14548-14553.
162. Musonda, C. C.; Whitlock, G. A.; Witty, M. J.; Brun, R.; Kaiser, M. Synthesis and evaluation of 2-pyridyl pyrimidines with in vitro antiplasmodial and antileishmanial activity. Bioorg. Med. Chem. Lett., 2009, 19(2), 401-405.
163. Mordmüller, B.; Fendel, R.; Kreidenweiss, A.; Gille, C.; Hurwitz, R.; Metzger, W. G.; Kun, J. F.; Lamkemeyer, T.; Nordheim, A.; Kremsner, P. G. Plasmodia express two threonine-peptidase complexes during asexual development. Mol. Biochem. Parasitol., 2006, 148(1), 79-85.
164. Ramasamy, G.; Gupta, D.; Mohmmed, A.; Chauhan, V. S. Characterization and localization of Plasmodium falciparum homolog of prokaryotic ClpQ/HslV protease. Mol. Biochem. Parasitol., 2007, 152(2), 139-148.
165. Gantt, S. M.; Myung, J. M.; Briones, M. R.; Li, W. D.; Corey, E. J.; Omura, S.; Nussenzweig, V.; Sinnis, P. Proteasome inhibitors block development of Plasmodium spp. Antimicrob. Agents Chemother., 1998, 42(10), 2731-2738.
166. Lindenthal, C.; Weich, N.; Chia, Y. S.; Heussler, V.; Klinkert, M. Q. The proteasome inhibitor MLN-273 blocks exoerythrocytic and erythrocytic development of Plasmodium parasites. Parasitology, 2005, 131(Pt 1), 37-44.
167. Reynolds, J. M.; El Bissati, K.; Brandenburg, J.; Gunzl, A.; Mamoun, C. B. Antimalarial activity of the anticancer and proteasome inhibitor bortezomib and its analog ZL3B. BMC Clin. Pharmacol., 2007, 7, 13.
168. Kreidenweiss, A.; Kremsner, P. G.; Mordmüller, B. Comprehensive study of proteasome inhibitors against Plasmodium falciparum laboratory strains and field isolates from Gabon. Malar. J., 2008, 7, 187.
169. Nezami, A.; Kimura, T.; Hidaka, K.; Kiso, A.; Liu, J.; Kiso, Y.; Goldberg, D. E.; Freire, E. High-affinity inhibition of a family of Plasmodium falciparum proteases by a designed adaptive inhibitor. Biochemistry, 2003, 42(28), 8459-8464.
170. Singh, A.; Rosenthal, P. J. Selection of cysteine protease inhibitor-resistant malaria parasites is accompanied by amplification of falcipain genes and alteration in inhibitor transport. J. Biol. Chem., 2004, 279(34), 35236-35241.
171. Singh, A.; Rosenthal, P. J. Comparison of efficacies of cysteine protease inhibitors against five strains of Plasmodium falciparum. Antimicrob. Agents Chemother., 2001, 45(3), 949-951.
172. Zhu, J.; Chen, T.; Chen, L.; Lu, W.; Che, P.; Huang, J.; Li, H.; Li, J.; Jiang, H. 2-amido-3-(1H-indol-3-yl)-N-substitued-propanamides as a new class of falcipain-2 inhibitors. 1. Design, synthesis, biological evaluation and binding model studies. Molecules, 2009, 14(1), 494-508.
173. Goud, P. M.; Sheri, A.; Desai, P. V.; Watkins, E. B.; Tekwani, B.; Sabnis, Y.; Gut, J.; Rosenthal, P. J.; Avery, M. A. Design, synthesis and evaluation of trisubstituted thiazoles targeting Plasmodium Falciparum cysteine proteases. Med. Chem. Res., 2005, 14(2), 74-105.
174. Batra, S.; Sabnis, Y. A.; Rosenthal, P. J.; Avery, M. A. Structure-based approach to falcipain-2 inhibitors: synthesis and biological evaluation of 1,6,7-Trisubstituted dihydroisoquinolines and isoquinolines. Bioorg. Med. Chem., 2003, 11(10), 2293-2299.
175. Hatabu, T.; Hagiwara, M.; Taguchi, N.; Kiyozawa, M.; Suzuki, M.; Kano, S.; Sato, K. Plasmodium falciparum: The fungal metabolite gliotoxin inhibits proteasome proteolytic activity and exerts a plasmodicidal effect on P. falciparum. Exp. Parasitol., 2006, 112(3), 179-183.