Plasmepsins inhibitors as potential drugs against malaria: Starving the parasite

Aspartic Acid Proteases as Therapeutic Targets

Volumn 45, Issue , 2011, Pages 549-571

  Gemma, Sandra ^a  

^a UNIVERSITY OF SIENA   (Italy)

Author keywords

Cathepsin D; Food vacuole; Hemoglobin; Plasmepsin

Indexed keywords

EID: 84857692223     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9783527630943.ch19     Document Type: Chapter

References (82)

1. World Malaria Report 2005, 36.
2. Hay, S.I., Guerra, C.A., Tatem, A.J., Noor, A.M., and Snow, R.W. (2004) The global distribution and population at risk of malaria: past, present, and future. Lancet Infectious Diseases, 4, 327-336.
3. Edwards, G.and Biagini, G.A. (2006) Resisting resistance: dealing with the irrepressible problem of malaria. British Journal of Clinical Pharmacology, 61, 690-693.
4. Arav-Boger, R.and Shapiro, T.A. (2005) Molecular mechanisms of resistance in antimalarial chemotherapy: the unmet challenge. Annual Review of Pharmacology and Toxicology, 45, 565-585.
5. Khan, S.M.and Waters, A.P. (2004) Malaria parasite transmission stages: an update. Trends in Parasitology, 20, 575-580.
6. Blackman, M.J. (2008) Malarial proteases and host cell egress: an 'emerging' cascade. Cellular Microbiology, 10, 1925-1934.
7. Ball, E.G., Mc, K.R., Anfinsen, C.B., Cruz, W.O., and Geiman, Q.M. (1948) Studies on malarial parasites; chemical and metabolic changes during growth and multiplication in vivo and in vitro. The Journal of Biological Chemistry, 175, 547-571.
8. Lew, V.L., Tiffert, T., and Ginsburg, H. (2003) Excess hemoglobin digestion and the osmotic stability of Plasmodium falciparum-infected red blood cells. Blood, 101, 4189-4194.
9. Banerjee, R., Liu, J., Beatty,W., Pelosof, L., Klemba, M., and Goldberg, D.E. (2002) Four plasmepsins are active in the Plasmodium falciparum food vacuole, including a protease with an active-site histidine. Proceedings of the National Academy of Sciences of the United States of America, 99, 990-995.
10. Gluzman, I.Y., Francis, S.E., Oksman, A., Smith, C.E., Duffin, K.L., and Goldberg, D.E. (1994) Order and specificity of the Plasmodium falciparum hemoglobin degradation pathway. The Journal of Clinical Investigation, 93, 1602-1608.
11. Goldberg, D.E., Slater, A.F., Beavis, R., Chait, B., Cerami, A., and Henderson, G.B. (1991) Hemoglobin degradation in the human malaria pathogen Plasmodium falciparum: a catabolic pathway initiated by a specific aspartic protease. The Journal of Experimental Medicine, 173, 961-969.
12. Goldberg, D.E. (1993) Hemoglobin degradation in Plasmodium-infected red blood cells. Seminars in Cell Biology, 4, 355-361.
13. Eggleson, K.K., Duffin, K.L., and Goldberg, D.E. (1999) Identification and characterization of falcilysin, a metallopeptidase involved in hemoglobin catabolism within the malaria parasite Plasmodium falciparum. The Journal of Biological Chemistry, 274, 32411-32417.
14. Francis, S.E., Gluzman, I.Y., Oksman, A., Banerjee, D., and Goldberg, D.E. (1996) Characterization of native falcipain, an enzyme involved in Plasmodium falciparum hemoglobin degradation. Molecular and Biochemical Parasitology, 83, 189-200.
15. Berry, C., Humphreys, M.J., Matharu, P., Granger, R., Horrocks, P., Moon, R.P., Certa, U., Ridley, R.G., Bur, D., and Kay, J. (1999) A distinct member of the aspartic proteinase gene family from the human malaria parasite Plasmodium falciparum. FEBS Letters, 447, 149-154.
16. Humphreys, M.J., Moon, R.P., Klinder, A., Fowler, S.D., Rupp, K., Bur, D., Ridley, R.G., and Berry, C. (1999) The aspartic proteinase from the rodent parasite Plasmodium berghei as a potential model for plasmepsins from the human malaria parasite, Plasmodium falciparum. FEBS Letters, 463, 43-48.
17. Westling, J., Yowell, C.A., Majer, P., Erickson, J.W., Dame, J.B., and Dunn, B.M. (1997) Plasmodium falciparum, P. vivax, and P. malariae: a comparison of the active site properties of plasmepsins cloned and expressed from three different species of the malaria parasite. Experimental Parasitology, 87, 185-193.
18. Rosenthal, P.J., McKerrow, J.H., Aikawa, M., Nagasawa, H., and Leech, J.H. (1988) Amalarial cysteine proteinase is necessary for hemoglobin degradation by Plasmodium falciparum. The Journal of Clinical Investigation, 82, 1560-1566.
19. Klemba, M., Gluzman, I., and Goldberg, D.E. (2004) A Plasmodium falciparum dipeptidyl aminopeptidase I participates in vacuolar hemoglobin degradation. The Journal of Biological Chemistry, 279, 43000-43007.
20. Olson, J.E., Lee, G.K., Semenov, A., and Rosenthal, P.J. (1999) Antimalarial effects in mice of orally administered peptidyl cysteine protease inhibitors. Bioorganic & Medicinal Chemistry, 7, 633-638.
21. Semenov, A., Olson, J.E., and Rosenthal, P.J. (1998) Antimalarial synergy of cysteine and aspartic protease inhibitors. Antimicrobial Agents and Chemotherapy, 42, 2254-2258.
22. Rosenthal, P.J. (1995) Plasmodium falciparum: effects of proteinase inhibitors on globin hydrolysis by cultured malaria parasites. Experimental Parasitology, 80, 272-281.
23. Davies, D.R. (1990) The structure and function of the aspartic proteinases. Annual Review of Biophysics and Biophysical Chemistry, 19, 189-215.
24. Northrop, D.B. (2001) Follow the protons: a low-barrier hydrogen bond unifies the mechanisms of the aspartic proteases. Accounts of Chemical Research, 34, 790-797.
25. Schechter, I.and Berger, A. (1967) On the size of the active site in proteases. I. Papain. Biochemical and Biophysical Research Communications, 27, 157-162.
26. Westling, J., Cipullo, P., Hung, S.H., Saft, H., Dame, J.B., and Dunn, B.M. (1999) Active site specificity of plasmepsin II. Protein Science: A Publication of the Protein Society, 8, 2001-2009.
27. Beyer, B.B., Johnson, J.V., Chung, A.Y., Li, T., Madabushi, A., Agbandje-McKenna, M., McKenna, R., Dame, J.B., and Dunn, B.M. (2005) Active-site specificity of digestive aspartic peptidases from the four species of Plasmodium that infect humans using chromogenic combinatorial peptide libraries. Biochemistry, 44, 1768-1779.
28. Li, T., Yowell, C.A., Beyer, B.B., Hung, S.H.,Westling, J., Lam, M.T., Dunn, B.M., and Dame, J.B. (2004) Recombinant expression and enzymatic subsite characterization of plasmepsin 4 from the four Plasmodium species infecting man. Molecular and Biochemical Parasitology, 135, 101-109.
29. Silva, A.M., Lee, A.Y., Gulnik, S.V., Maier, P., Collins, J., Bhat, T.N., Collins, P.J., Cachau, R.E., Luker, K.E., Gluzman, I.Y., Francis, S.E., Oksman, A., Goldberg, D.E., and Erickson, J.W. (1996) Structure and inhibition of plasmepsin II, a hemoglobindegrading enzyme from Plasmodium falciparum. Proceedings of the National Academy of Sciences of the United States of America, 93, 10034-10039.
30. Liu, J., Gluzman, I.Y., Drew, M.E., and Goldberg, D.E. (2005) The role of Plasmodium falciparum food vacuole plasmepsins. The Journal of Biological Chemistry, 280, 1432-1437.
31. Asojo, O.A., Afonina, E., Gulnik, S.V., Yu, B., Erickson, J.W., Randad, R., Medjahed, D., and Silva, A.M. (2002) Structures of Ser205 mutant plasmepsin II from Plasmodium falciparum at 1.8 Angstrom in complex with the inhibitors rs367 and rs370. Acta Crystallographica. Section D, Biological Crystallography, 58, 2001-2008.
32. Asojo, O.A., Gulnik, S.V., Afonina, E., Yu, B., Ellman, J.A., Haque, T.S., and Silva, A.M. (2003) Novel uncomplexed and complexed structures of plasmepsin II, an aspartic protease from Plasmodium falciparum. Journal of Molecular Biology, 327, 173-181.
33. Bernstein, N.K., Cherney, M.M., Loetscher, H., Ridley, R.G., and James, M.N. (1999) Crystal structure of the novel aspartic proteinase zymogen proplasmepsin II from Plasmodium falciparum. Nature Structural Biology, 6, 32-37.
34. Bernstein, N.K., Cherney, M.M., Yowell, C.A., Dame, J.B., and James, M.N. (2003) Structural insights into the activation of P. vivax plasmepsin. Journal of Molecular Biology, 329, 505-524.
35. 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., and McKenna, R. (2006) Structure of the aspartic protease plasmepsin 4 from the malarial parasite Plasmodium malariae bound to an allophenylnorstatine-based inhibitor. Acta Crystallographica. Section D, Biological Crystallography, 62, 246-252.
36. Cunico, W., Gomes, C.R.B., Harrison, W.T.A., Moreth, M., Wardell, J.L., and Wardell, S.M.S.V. (2009) Structures of three (2R,3S)-4-(arylmethyl)-1-(4-phenyl-3-amino-2-hydroxy-butyl)-piperazine derivatives, potential anti-malarial agents. Zeitschrift Fur Kristallographie, 224, 461-470.
37. Johansson, P.O., Lindberg, J., Blackman, M.J., Kvarnstrom, I., Vrang, L.,Hamelink, E., Hallberg, A., Rosenquist, A., and Samuelsson, B. (2005) Design and synthesis of potent inhibitors of plasmepsin I and II: X-ray crystal structure of inhibitor in complex with plasmepsin II. Journal of Medicinal Chemistry, 48, 4400-4409.
38. Prade, L., Jones, A.F., Boss, C., Bildstein, S.R., Meyer, S., Binkert, C., and Bur, D. (2005) X-ray structure of plasmepsin II complexed with a potent achiral inhibitor. The Journal of Biological Chemistry, 280, 23837-23843.
39. Robbins, A.H., Dunn, B.M., Agbandje-McKenna, M., and McKenna, R. (2009) Crystallographic evidence for noncoplanar catalytic aspartic acids in plasmepsin II resides in the Protein Data Bank. Acta Crystallographica. Section D, Biological Crystallography, 65, 294-296.
40. Binkert, C., Frigerio, M., Jones, A.,Meyer, S., Pesenti, C., Prade, L., Viani, F., and Zanda, M. (2006) Replacement of isobutyl by trifluoromethyl in pepstatin A selectively affects inhibition of aspartic proteinases. ChemBioChem, 7, 181-186.
41. Carroll, C.D., Patel, H., Johnson, T.O., Guo,T., Orlowski, M.,He, Z.M.,Cavallaro, C.L., Guo, J., Oksman, A., Gluzman, I.Y., Connelly, J., Chelsky, D., Goldberg, D.E., and Dolle, R.E. (1998) Identification of potent inhibitors of Plasmodium falciparum plasmepsin II from an encoded statine combinatorial library. Bioorganic & Medicinal Chemistry Letters, 8, 2315-2320.
42. Carroll, C.D., Johnson, T.O., Tao, S., Lauri, G., Orlowski, M., Gluzman, I.Y., Goldberg, D.E., and Dolle, R.E. (1998) Evaluation of a structure-based statine cyclic diamino amide encoded combinatorial library against plasmepsin II and cathepsin D. Bioorganic & Medicinal Chemistry Letters, 8, 3203-3206.
43. Molteni, M., Pesenti, C., Sani, M., Volonterio, A., and Zanda, M. (2004) Fluorinated peptidomimetics: synthesis, conformational and biological features. Journal of Fluorine Chemistry, 125, 1735-1743.
44. Haque, T.S., Skillman, A.G., Lee, C.E., Habashita, H., Gluzman, I.Y., Ewing, T.J.A., Goldberg, D.E., Kuntz, I.D., and Ellman, J.A. (1999) Potent, low-molecularweight non-peptide inhibitors of malarial aspartyl protease plasmepsin II. Journal of Medicinal Chemistry, 42, 1428-1440.
45. Weik, S., Luksch, T., Evers, A., Bottcher, J., Sotriffer, C.A., Hasilik, A., Loffler, H.G., Klebe, G., and Rademann, J. (2006) The potential of P1 site alterations in peptidomimetic protease inhibitors as suggested by virtual screening and explored by the use of C-C-coupling reagents. ChemMedChem, 1, 445-457.
46. Noteberg, D., Hamelink, E., Hulten, J., Wahlgren, M., Vrang, L., Samuelsson, B., and Hallberg, A. (2003) Design and synthesis of plasmepsin I and plasmepsin II inhibitors with activity in Plasmodium falciparum-infected cultured human erythrocytes. Journal of Medicinal Chemistry, 46, 734-746.
47. Noteberg, D., Schaal, W., Hamelink, E., Vrang, L., and Larhed, M. (2003) Highspeed optimization of inhibitors of the malarial proteases plasmepsin I and II. Journal of Combinatorial Chemistry, 5, 456-464.
48. Muthas, D., Noteberg, D., Sabnis, Y.A., Hamelink, E., Vrang, L., Samuelsson, B., Karlen, A., and Hallberg, A. (2005) Synthesis, biological evaluation, and modeling studies of inhibitors aimed at the malarial proteases plasmepsins I and II. Bioorganic & Medicinal Chemistry, 13, 5371-5390.
49. Oscarsson, K., Oscarson, S., Vrang, L., Hamelink, E., Hallberg, A., and Samuelsson, B. (2003) New potent C-2-symmetric malaria plasmepsin I and II inhibitors. Bioorganic & Medicinal Chemistry, 11, 1235-1246.
50. Ersmark, K., Feierberg, I., Bjelic, S., Hulten, J., Samuelsson, B., Aqvist, J., and Hallberg, A. (2003) C-2-symmetric inhibitors of Plasmodium falciparum plasmepsin II: synthesis and theoretical predictions. Bioorganic & Medicinal Chemistry, 11, 3723-3733.
51. Ersmark, K., Feierberg, I., Bjelic, S., Hamelink, E.,Hackett, F., Blackman, M.J., Hulten, J., Samuelsson, B., Aqvist, J., and Hallberg, A. (2004) Potent inhibitors of the Plasmodium falciparum enzymes plasmepsin I and II devoid of cathepsin D inhibitory activity. Journal of Medicinal Chemistry, 47, 110-122.
52. Ersmark, K., Nervall, M., Hamelink, E., Janka, L.K., Clemente, J.C., Dunn, B.M., Blackman, M.J., Samuelsson, B., Aqvist, J., and Hallberg, A. (2005) Synthesis of malarial plasmepsin inhibitors and prediction of binding modes by molecular dynamics simulations. Journal of Medicinal Chemistry, 48, 6090-6106.
53. Gutierrez-de-Teran, H., Nervall, M., Ersmark, K., Liu, P., Janka, L.K., Dunn, B., Hallberg, A., and Aqvist, J. (2006) Inhibitor binding to the plasmepsin IV aspartic protease from Plasmodium falciparum. Biochemistry, 45, 10529-10541.
54. Ersmark, K., Nervall, M., Gutierrez-de-Teran, H., Hamelink, E., Janka, L.K., Clemente, J.C., Dunn, B.M., Gogoll, A., Samuelsson, B., Aqvist, J., and Hallberg, A. (2006) Macrocyclic inhibitors of the malarial aspartic proteases plasmepsin I, II, and IV. Bioorganic & Medicinal Chemistry, 14, 2197-2208.
55. Dahlgren, A., Kvarnstrom, I., Vrang, L., Hamelink, E., Hallberg, A., Rosenquist, A., and Samuelsson, B. (2003) New inhibitors of the malaria aspartyl proteases plasmepsin I and II. Bioorganic & Medicinal Chemistry, 11, 3423-3437.
56. Dahlgren, A., Kvarnstrom, I., Vrang, L., Hamelink, E., Hallberg, A., Rosenquist, A., and Samuelsson, B. (2003) Solid-phase library synthesis of reversed-statine type inhibitors of the malarial aspartyl proteases plasmepsin I and II. Bioorganic & Medicinal Chemistry, 11, 827-841.
57. Orrling, K.M., Marzahn, M.R., Gutierrezde-Teran, H., Aqvist, J., Dunn, B.M., and Larhed, M. (2009) alpha-Substituted norstatines as the transition-state mimic in inhibitors of multiple digestive vacuole malaria aspartic proteases. Bioorganic & Medicinal Chemistry, 17, 5933-5949.
58. Nezami, A., Luque, I., Kimura, T., Kiso, Y., and Freire, E. (2002) Identification and characterization of allophenylnorstatinebased inhibitors of plasmepsin II, an antimalarial target. Biochemistry, 41, 2273-2280.
59. Nezami, A., Kimura, T., Hidaka, K., Kiso, A., Liu, J., Kiso, Y., Goldberg, D.E., and Freire, E. (2003)High-affinity inhibition of a family of Plasmodium falciparum proteases by a designed adaptive inhibitor. Biochemistry, 42, 8459-8464.
60. Nezami, A.and Freire, E. (2002) The integration of genomic and structural information in the development of high affinity plasmepsin inhibitors. International Journal for Parasitology, 32, 1669-1676.
61. Kiso, A., Hidaka, K., Kimura, T., Hayashi, Y., Nezami, A., Freire, E., and Kiso, Y. (2004) Search for substrate-based inhibitors fitting the S20 space of malarial aspartic protease plasmepsin II. Journal of Peptide Science, 10, 641-647.
62. Hidaka, K., Kimura, T., Tsuchiya, Y., Kamiya, M., Ruben, A.J., Freire, E., Hayashi, Y., and Kiso, Y. (2007) Additional interaction of allophenylnorstatinecontaining tripeptidomimetics with malarial aspartic protease plasmepsin II. Bioorganic & Medicinal Chemistry Letters, 17, 3048-3052.
63. Hidaka, K., Kimura, T., Ruben, A.J., Uemura, T., Kamiya, M., Kiso, A., Okamoto, T., Tsuchiya, Y., Hayashi, Y., Freire, E., and Kiso, Y. (2008) Antimalarial activity enhancement in hydroxymethylcarbonyl (HMC) isosterebased dipeptidomimetics targeting malarial aspartic protease plasmepsin. Bioorganic & Medicinal Chemistry, 16, 10049-10060.
64. Degliesposti, G., Kasam, V., Da Costa, A., Kang, H.K., Kim, N., Kim, D.W., Breton, V., Kim, D., and Rastelli, G. (2009) Design and discovery of plasmepsin II inhibitors using an automated workflow on largescale grids. ChemMedChem, 4, 1164-1173.
65. Friedman, R.and Caflisch, A. (2009) Discovery of plasmepsin inhibitors by fragment-based docking and consensus scoring. ChemMedChem, 4, 1317-1326.
66. Azim, M.K., Ahmed, W., Khan, I.A., Rao, N.A., and Khan, K.M. (2008) Identification of acridinyl hydrazides as potent aspartic protease inhibitors. Bioorganic & Medicinal Chemistry Letters, 18, 3011-3015.
67. Boss, C., Richard-Bildstein, S., Weller, T., Fischli, W., Meyer, S., and Binkert, C. (2003) Inhibitors of the Plasmodium falciparum parasite aspartic protease plasmepsin II as potential antimalarial agents. Current Medicinal Chemistry, 10, 883-907.
68. Corminboeuf, O., Dunet, G., Hafsi, M., Grimont, J., Grisostomi, C., Meyer, S., Binkert, C., Bur, D., Jones, A., Prade, L., Brun, R., and Boss, C. (2006) Inhibitors of plasmepsin II-potential antimalarial agents. Bioorganic & Medicinal Chemistry Letters, 16, 6194-6199.
69. Jiang, S.P., Prigge, S.T.,Wei, L., Gao, Y.E., Hudson, T.H., Gerena, L., Dame, J.B., and Kyle, D.E. (2001) New class of small nonpeptidyl compounds blocks Plasmodium falciparum development in vitro by inhibiting plasmepsins. Antimicrobial Agents and Chemotherapy, 45, 2577-2584.
70. Mueller, R., Huerzeler, M., and Boss, C. (2003) Synthesis of plasmepsin II inhibitors-potential antimalarial agents. Molecules, 8, 556-564.
71. Azim, M.K., Ahmed, W., Khan, I.A., Rao, N.A., and Khan, K.M. (2008) Identification of acridinyl hydrazides as potent aspartic protease inhibitors. Bioorganic & Medicinal Chemistry Letters, 18, 3011-3015.
72. Boss, C., Corminboeuf, O., Grisostomi, C., Meyer, S., Jones, A.F., Prade, L., Binkert, C., Fischli,W.,Weller, T., and Bur, D. (2006) Achiral, cheap, and potent inhibitors of plasmepsins I, II, and IV. ChemMedChem, 1, 1341-1345.
73. Brass, S., Chan, N.S., Gerlach, C., Luksch, T., Bottcher, J., and Diederich,W.E. (2006) Synthesis of 2,3,4,7-tetrahydro-1Hazepines as privileged ligand scaffolds for the design of aspartic protease inhibitors via a ring-closing metathesis approach. Journal of Organometallic Chemistry, 691, 5406-5422.
74. Luksch, T., Chan, N.S., Brass, S., Sotriffer, C.A., Klebe, G., and Diederich,W.E. (2008) Computer-aided design and synthesis of nonpeptidic plasmepsin II and IV inhibitors. ChemMedChem, 3, 1323-1336.
75. Carcache, D.A., Hortner, S.R., Bertogg, A., Binkert, C., Bur, D.,Marki, H.P., Dorn, A., and Diederich, F. (2002) De novo design, synthesis, and in vitro evaluation of a new class of nonpeptidic inhibitors of the malarial enzyme plasmepsin II. ChemBioChem, 3, 1137-1141.
76. Carcache, D.A., Hortner, S.R., Bertogg, A., Diederich, F., Dorn, A., Marki, H.P., Binkert, C., and Bur, D. (2003) A new class of inhibitors for the malarial aspartic protease plasmepsin II based on a central 11-azatricyclo[6.2.1.0(2,7)]undeca-2,4,6-triene scaffold.Helvetica Chimica Acta, 86, 2192-2209.
77. Carcache, D.A., Hortner, S.R., Seiler, P., Diederich, F., Dorn, A., Marki, H.P., Binkert, C., and Bur, D. (2003) Development of a new class of inhibitors for the malarial aspartic protease plasmepsin II based on a central 7-azabicyclo[2.2.1]heptane scaffold. Helvetica Chimica Acta, 86, 2173-2191.
78. Hof, F., Schutz, A., Fah, C.,Meyer, S., Bur, D., Liu, J., Goldberg, D.E., and Diederich, F. (2006) Starving the malaria parasite: inhibitors active against the aspartic proteases plasmepsins I, II, and IV. Angewandte Chemie (International Ed. in English), 45, 2138-2141.
79. Zurcher, M., Gottschalk, T.,Meyer, S., Bur, D., and Diederich, F. (2008) Exploring the flap pocket of the antimalarial target plasmepsin II: the 55% rule? applied to enzymes. ChemMedChem, 3, 237-240.
80. Romeo, S., Dell'Agli, M., Parapini, S., Rizzi, L., Galli, G., Mondani, M., Sparatore, A., Taramelli, D., and Bosisio, E. (2004) Plasmepsin II inhibition and antiplasmodial activity of primaquine-statine ?double-drugs?. Bioorganic & Medicinal Chemistry Letters, 14, 2931-2934.
81. Dell'Agli, M., Parapini, S., Galli, G., Vaiana, N., Taramelli, D., Sparatore, A., Liu, P., Dunn, B.M., Bosisio, E., and Romeo, S. (2006) High antiplasmodial activity of novel plasmepsins I and II inhibitors. Journal of Medicinal Chemistry, 49, 7440-7449.
82. Romeo, S., Parapin, S., Dell'Agli, M., Vaiana, N., Magrone, P., Galli, G., Sparatore, A., Taramelli, D., and Bosisio, E. (2008) Atovaquone-statine 'doubledrugs' with high antiplasmodial activity. ChemMedChem, 3, 418-420.