Summary
Cysteine proteinases of protozoan and helminth parasites are considered to have a high potential as targets for novel antiparasite agents. This has stimulated research on the enzymes and a large body of data has now been accumulated. This Perspective provides an overview of the current situation, with recent advances being highlighted. Emphasis is given to the Type I cysteine proteinases of trypanosomatid protozoa, which are atypical in having an extra C-terminal domain, and the asparaginyl endopeptidase ofSchistosoma, for which the only homologues known are those in plants. The locations of parasite cysteine proteinases are described, with emphasis on the extralysosomal sites, and the putative roles of the enzymes in host-parasite interactions, including parasite nutrition and host invasion, are discussed. The major advances being made in elucidating cysteine proteinase function in protozoan parasites through genetic manipulation, including targeted gene deletion, are presented, with the Type I cysteine proteinases ofLeishmania being used as an example. The importance of this approach in the validation of the enzymes as drug targets is discussed. The current status of attempts to exploit parasite cysteine proteinases with drugs is presented, and future prospects are outlined.
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North, M.J., Mottram, J.C. and Coombs, G.H., Parasitol. Today, 6 (1990) 270.
McKerrow, J.H., Sun, E., Rosenthal, P.J. and Bouvier, J., Annu. Rev. Microbiol., 47 (1993) 821.
Coombs, G.H. and Mottram, J.C., In Hide, G., Mottram, J.C., Coombs, G.H. and Holmes, P.H. (Eds.) Trypanosomiasis and Leishmaniasis: Biology and Control, CAB International, Oxford, U.K., 1996, pp. 177–197.
Protease Inhibition as a Target for Parasite Chemotherapy, WHO TDR, San Francisco, 1995.
McKerrow, J.H., Perspect. Drug Discov. Design, 2 (1994) 437.
Mallinson, D.J., Livingstone, J., Appleton, K.M., Lees, S.J., Coombs, G.H. and North, M.J., Microbiology, 141 (1995) 3077.
Mallinson, D.J., Lockwood, B.C., Coombs, G.H. and North, M.J., J. Gen. Microbiol. 140, (1994) 2725.
Provenzano, D. and Alderete, J.F., Infect. Immun., 63 (1995) 3388.
Keene, W.E., Petitt, M.G., Allen, S. and McKerrow, J.H., J. Exp. Med., 163 (1986) 536.
Schulte, W. and Scholze, H., J. Protozool., 36 (1989) 538.
Nesterenko, M.V., Tilley, M. and Upton, S.J., Microbios, 83 (1995) 77.
Michalski, W.P., Crooks, J.K. and Prowse, S.J., Int. J. Parasitol., 24 (1994) 189.
Choi, W.-Y., Nam, H.-W. and Youn, J.-H., Korean J. Parasitol., 27 (1989) 161.
Aldape, K., Huizinga, H., Bouvier, J. and McKerrow, J., Exp. Parasitol., 78 (1994) 230.
Liu, D.W., Kato, H., Nakamura, T. and Sugane, K., Mol. Biochem. Parasitol., 76 (1996) 11.
Todorova, V.K., Knox, D.P. and Kennedy, M.W., Parasitology, 111 (1995) 201.
Dowd, A.J., McGonigle, S. and Dalton, J.P., Eur. J. Biochem., 232 (1995) 241.
Brown, A., Burleigh, J.M., Billett, E.E. and Pritchard, D.I., Parasitology, 110 (1995) 555.
Maki, J. and Yanagisawa, T.J., Helminth, 60 (1986) 31.
Cox, G.N., Pratt, D., Hageman, R. and Boisvenue, R.J., Mol. Biochem. Parasitol., 41 (1990) 25.
Cazzulo, J.J., Couso, R., Raimondi, A., Wernstedt, C. and Hellman, U., Mol. Biochem. Parasitol., 33 (1989) 33.
Robertson, C.D. and Coombs, G.H., Mol. Biochem. Parasitol., 42 (1990) 269.
Robertson, C.D. and Coombs, G.H., Microbiology, 140 (1994) 417.
Harth, G., Andrews, N., Mills, A.A., Engel, J.C., Smith, R. and McKerrow, J.H., Mol. Biochem. Parasitol., 58 (1993) 17.
Meirelles, M.N.L., Juliano, L., Carmona, E., Silva, S.G., Costa, E.M., Murta, A.C.M. and Scharfstein, J., Mol. Biochem. Parasitol., 52 (1992) 175.
Franke de Cazzulo, B.M., Martínez, J., North, M.J., Coombs, G.H. and Cazzulo, J.J., FEMS Microbiol. Lett., 124 (1994) 81.
Eakin, A.E., Mills, A.A., Harth, G., McKerrow, J.H. and Craik, C.S., J. Biol. Chem., 267 (1992) 7411.
Campetella, O., Henriksson, J., Aslund, L., Frasch, A.C.C., Pettersson, U. and Cazzulo, J.J., Mol. Biochem. Parasitol., 50 (1992) 225.
Mottram, J.C., Souza, A.E., Hutchison, J.E., Carter, R., Frame, M.J. and Coombs, G.H., Proc. Natl. Acad. Sci. USA, 93 (1996) 6008.
Souza, A.E., Waugh, S., Coombs, G.H. and Mottram, J.C., FEBS Lett., 311 (1992) 124.
Mottram, J.C., North, M.J., Barry, J.D. and Coombs, G.H., FEBS Lett., 258 (1989) 211.
Parodi, A.J., Labriola, C. and Cazzulo, J.J., Mol. Biochem. Parasitol., 69 (1995) 247.
Labriola, C., Cazzulo, J.J. and Parodi, A.J., J. Cell Biol., 130 (1995) 771.
Martinez, J., Campetella, O., Frasch, A.C.C. and Cazzulo, J.J., Immunol. Lett., 35 (1993) 191.
Pamer, E.G., Davis, C.E. and So, M., Infect. Immun., 59 (1991) 1074.
Eakin, A.E., McGrath, M.E., McKerrow, J.H., Fletterick, R.J. and Craik, C.S., J. Biol. Chem., 268 (1993) 6115.
Duboise, S.M., Vannier-Santos, M.A., Costa-Pinto, D., Rivas, L., Pan, A.A., Traub-Cseko, Y.M., de Souza, W. and McMahon-Pratt, D., Mol. Biochem. Parasitol., 68 (1994) 119.
North, M.J., Parasitol. Today, 7 (1991) 249.
Lima, A.P.C.A., Tessier, D.C., Thomas, D.Y., Scharfstein, J., Storer, A.C. and Vernet, T., Mol. Biochem. Parasitol., 67 (1994) 333.
Mottram, J.C., Robertson, C.D., Coombs, G.H. and Barry, J.D., Mol. Microbiol., 6 (1992) 1925.
Traub-Cseko, Y.M., Duboise, M., Boukai, L.K. and McMahon-Pratt, D., Mol. Biochem. Parasitol., 57 (1993) 101.
Bart, G., Coombs, G.H. and Mottram, J.C., Mol. Biochem. Parasitol., 73 (1995) 271.
Robertson, C.D. and Coombs, G.H., Mol. Biochem. Parasitol., 62 (1993) 271.
Davis, A.H., Nanduri, J. and Watson, D.C., J. Biol. Chem., 262 (1987) 12851.
Ishii, S., Methods Enzymol., 244 (1994) 604.
Gotz, B. and Klinkert, M.Q., Biochem. J., 290 (1993) 801.
Takeda, O., Miura, Y., Mitta, M., Matsushita, H., Kato, I., Abe, Y., Yokosawa, H. and Ishii, S., J. Biochem., 116 (1994) 541.
Becker, C., Shutov, A.D., Nong, V.H., Senyuk, V.I., Jung, R., Horstmann, C., Fischer, J., Nielsen, N.C. and Muntz, K., Eur. J. Biochem., 228 (1995) 456.
Dalton, J.P., Hola-Jamriska, L. and Brindley, P.J., Parasitology, 111 (1995) 575.
Hara-Nishimura, I., Shimada, T., Hiraiwa, N. and Nishimura, M., J. Plant Physiol., 145 (1995) 632.
Dalton, J.P. and Brindley, P.J., Parasitol. Today, 12 (1996) 125.
Lawrence, J.D., J. Parasitol., 59 (1973) 60.
Zussman, R.A., Bauman, P.M. and Petruska, J.C., J. Parasitol., 56 (1970) 75.
Dresden, M.H. and Deelder, A.M., Exp. Parasitol., 48 (1979) 190.
Smith, A.M., Dalton, J.P., Clough, K.A., Kilbane, C.L., Harrop, S.A., Hole, N. and Brindley, P.J., Mol. Biochem. Parasitol., 67 (1994) 11.
Becker, M.M., Harrop, S.A., Dalton, J.P., Kalinna, B.H., McManus, D.P. and Brindley, P.J., J. Biol. Chem., 270 (1995) 24496.
Butler, R., Michel, A., Kunz, W. and Klinkert, M.Q., Protein Pept. Lett., 2 (1995) 313.
Bontempi, E., Martinez, J. and Cazzulo, J.J., Mol. Biochem. Parasitol., 33 (1989) 43.
Souto-Padron, T., Campetella, O.E., Cazzulo, J.J. and de Souza, W., J. Cell Sci., 96 (1990) 485.
Mbawa, Z.R., Webster, P. and Lonsdale-Eccles, J.D., Eur. J. Cell Biol., 56 (1991) 243.
Rosenthal, P.J., McKerrow, J.H., Aikawa, M., Nagasawa, H. and Leech, J.H., J. Clin. Invest., 82 (1988) 1560.
Ostoa-Saloma, P., Cabrera, N., Becker, I. and Perez-Montfort, R., Mol. Biochem. Parasitol., 32 (1989) 133.
Lockwood, B.C., North, M.J. and Coombs, G.H., Mol. Biochem. Parasitol., 30 (1988) 135.
Parenti, D.M., J. Infect. Dis., 160 (1989) 1076.
Pupkis, M.F., Tetley, L. and Coombs, G.H., Exp. Parasitol., 62 (1986) 29.
Pupkis, M.F. and Coombs, G.H., J. Gen. Microbiol., 130 (1984) 2375.
Murta, A.C.M., Persechini, P.M., Padron, T.D., de Souza, W., Guimaraes, J.A. and Scharfstein, J., Mol. Biochem. Parasitol., 43 (1990) 27.
McGrath, M.E., Eakin, A.E., Engel, J.C., McKerrow, J.H., Craik, C.S. and Fletterick, R.J., J. Mol. Biol., 247 (1995) 251.
Arnholdt, A.C.V., Piuvezam, M.R., Russo, D.M., Lima, A.P.C.A., Pedrosa, R.C., Reed, S.G. and Scharfstein, J., J. Immunol., 151 (1993) 3171.
Fresno, M., Hernandezmunain, C., Dediego, J., Rivas, L., Scharfstein, J. and Bonay, P., Braz. J. Med. Biol. Res., 27 (1994) 431.
Yokoyama-Yasunaka, J.K.U., Pral, E.M.F., Oliveira, O.C., Alfieri, S.C. and Stolf, A.M.S., Acta Trop., 57 (1994) 307.
Ilg, T., Fuchs, M., Gnau, V., Wolfram, M., Harbecke, D. and Overath, P., Mol. Biochem. Parasitol., 67 (1994) 193.
Leippe, M., Sievertsen, H.J., Tannich, E. and Horstmann, R.D., Parasitology, 111 (1995) 569.
Bozner, P. and Demes, P., Parasitology, 102 (1991) 113.
Garber, G.E. and Lemchuk-Favel, L.T., Can. J. Microbiol., 35 (1989) 903.
North, M.J., Robertson, C.D. and Coombs, G.H., Mol. Biochem. Parasitol., 39 (1990) 183.
Luaces, A.L. and Barrett, A.J., Biochem. J., 250 (1988) 903.
Reed, S., Bouvier, J., Pollack, A.S., Engel, J.C., Brown, M., Hirata, K., Que, X.C., Eakin, A., Hagblom, P., Gillin, F. and McKerrow, J.H., J. Clin. Invest., 91 (1993) 1532.
Tannich, E., Scholze, H., Nickel, R. and Horstmann, R.D., J. Biol. Chem., 266 (1991) 4798.
Alderete, J.F., Newton, E., Dennis, C. and Neale, K.A., Genitourin. Med., 67 (1991) 331.
Bozner, P., Gombosova, A., Valent, M., Demes, P. and Alderete, J.F., Parasitology, 105 (1992) 387.
Garber, G.E. and Lemchukfavel, L.T., Parasitol. Res., 80 (1994) 361.
Scott, D.A., North, M.J. and Coombs, G.H., Int. J. Parasitol., 25 (1995) 657.
Scott, D.A., North, M.J. and Coombs, G.H., Exp. Parasitol., 80 (1995) 345.
Keene, W.E., Hidalgo, M.E., Orozco, E. and McKerrow, J.H., Exp. Parasitol., 71 (1990) 199.
Navarro-Garcia, F., Chavez-Duenas, L., Tsutsumi, V., Delrio, F.P. and Lopez-Revilla, R., Exp. Parasitol., 80 (1995) 361.
Perez-Tamayo, R., Becker, I., Montfort, I., Ostoa-Saloma, P. and Perez-Montfort, R., Parasitol. Res., 77 (1991) 192.
Reed, S.L., Keene, W.E. and McKerrow, J.H., J. Clin. Microbiol., 27 (1989) 2772.
Montfort, I., Pereztamayo, R., Canto, A.G., Deleon, M.D.G., Olivos, A. and Tello, E., J. Parasitol., 79 (1993) 98.
Bruchhaus, I. and Tannich, E., Parasitol. Res., 82 (1996) 189.
Arroyo, R. and Alderete, J.F., Infect. Immun., 57 (1989) 2991.
Avila, E.E. and Calderon, J., Exp. Parasitol., 76 (1993) 232.
Mitro, K., Bhagavathiammai, A., Zhou, O.M., Bobbett, G., McKerrow, J.H., Chokshi, R., Chokshi, B. and James, E.R., Exp. Parasitol., 78 (1994) 377.
Kamata, I., Yamada, M., Uchikawa, R., Matsuda, S. and Arizono, N., Clin. Exp. Immunol., 102 (1995) 71.
Gao, C.Y. and Zelenka, P.S., Exp. Cell Res., 219 (1995) 612.
Authié, E., Duvallet, G., Robertson, C. and Williams, D.J.L., Parasite Immunol., 15 (1993) 465.
Dalton, J.P., Smith, A.M., Clough, K.A. and Brindley, P.J., Parasitol. Today, 11 (1995) 299.
Rosenthal, P.J., Ring, C.S., Chen, X. and Cohen, F.E., J. Mol. Biol., 241 (1994) 312.
Rosenthal, P.J., Exp. Parasitol., 80 (1995) 272.
Rhoads, M.L. and Fetterer, R.H., J. Parasitol., 81 (1995) 505.
Dowd, A.J., Dalton, J.P., Loukas, A.C., Prociv, P. and Brindley, P.J., Am. J. Trop. Med. Hyg., 51 (1994) 341.
Harrop, S.A., Sawangjaroen, N., Prociv, P. and Brindley, P.J., Mol. Biochem. Parasitol., 71 (1995) 163.
Ray, C. and McKerrow, J.H., Mol. Biochem. Parasitol., 51 (1992) 239.
Larminie, C.G.C. and Johnstone, I.L., DNA Cell Biol., 15 (1996) 75.
Yamasaki, H., Kominami, E. and Aoki, T., Parasitol. Res., 78 (1992) 574.
Richer, J.K., Hunt, W.G., Sakanari, J.A. and Grieve, R.B., Exp. Parasitol., 76 (1993) 221.
Michel, A., Ghoneim, H., Resto, M., Klinkert, M.Q. and Kunz, W., Mol. Biochem. Parasitol., 73 (1995) 7.
Wasilewski, M.M., Lim, K.C., Phillips, J. and McKerrow, J.H., Mol. Biochem. Parasitol., 81 (1996) 179.
Klinkert, M.Q. and Kunz, W., Parasitol. Today, 12 (1996) 165.
Dalton, J.P. and Brindley, P.J., Parasitol. Today, 12 (1996) 165.
Wijffels, G.L., Salvatore, L., Dosen, M., Waddington, J., Wilson, L., Thompson, C., Campbell, N., Sexton, J., Wicker, J., Bowen, F., Friedel, T. and Spithill, T.W., Exp. Parasitol., 78 (1994) 132.
Newport, G.R., McKerrow, J.H., Hedstrom, R., Petit, M., McGarrigle, L., Barr, P.J. and Agabian, N., J. Biol. Chem., 263 (1988) 13179.
Talamas-Rohana, P. and Meza, I., J. Cell Biol., 106 (1988) 1787.
Vazquez, J., Franco, E., Reyes, G. and Meza, I., Cell Motil. Cytoskeleton, 32 (1995) 37.
Demeester, F., Shaw, E., Scholze, H., Stolarsky, T. and Mirelman, D., Infect. Immun., 58 (1990) 1396.
Fuller, J.D. and McDougald, L.R., J. Parasitol., 76 (1990) 464.
McKerrow, J.H., McGrath, M.E. and Engel, J.C., Parasitol. Today, 11 (1995) 279.
Cruz, A., Coburn, C.M. and Beverley, S.M., Proc. Natl. Acad. Sci. USA, 88 (1991) 7170.
Souza, A.E., Bates, P.A., Coombs, G.H. and Mottram, J.C., Mol. Biochem. Parasitol., 63 (1994) 213.
Hunter, C.A., Lockwood, B.C. and Coombs, G.H., Int. J. Parasitol., 22 (1992) 711.
Tomás, A.M. and Kelly, J.M., Mol. Biochem. Parasitol., 76 (1996) 91.
Engel, J.C. and McKerrow, J.H., Mem. Inst. Oswaldo Cruz, 90 (Suppl. I) (1995) 43.
Rosenthal, P.J., Lee, G.K. and Smith, R.E., J. Clin. Invest., 91 (1993) 1052.
Ring, C.S., Sun, E., McKerrow, J.H., Lee, G.K., Rosenthal, P.J., Kuntz, I.D. and Cohen, F.E., Proc. Natl. Acad. Sci. USA, 90 (1993) 3583.
Li, R., Kenyon, G.L., Cohen, F.E., Chen, X., Gong, B., Dominguez, J.N., Davidson, E., Kurzban, G., Miller, R.E., Nuzum, E.O., Rosenthal, P.J. and McKerrow, J.H., J. Med. Chem., 38 (1995) 5031.
Venegas, J. and Solari, A., Mol. Biochem. Parasitol., 73 (1995) 53.
Chen, M., Theander, T.G., Brogger Christensen, S., Hviid, L., Zhai, L. and Kharazmi, A., Antimicrob. Agents Chemother., 38 (1994) 1470.
Chen, M., Brogger Christensen, S., Blom, J., Lemmich, E., Nadelmann, L., Fich, K., Theander, T.G. and Kharazmi, A., Antimicrob. Agents Chemother., 37 (1993) 2550.
Zhai, L., Blom, J., Chen, M., Brogger Christensen, S. and Kharazmi, A., Antimicrob. Agents Chemother., 39 (1995) 2742.
Smith, A.M., Carmona, C., Dowd, A.J., McGonigle, S., Acosta, D. and Dalton, J.P., Parasite Immunol., 16 (1994) 325.
Urwin, P.E., Atkinson, H.J., Waller, D.A. and McPherson, M.J., Plant J., 8 (1995) 121.
Bremner, A.F., Coombs, G.H. and North, M.J., IRCS Med. Sci., 14 (1986) 555.
Yu, D., Wang, C.C. and Wang, A.L., J. Virol., 69 (1995) 2825.
Irvine, J.W., Coombs, G.H. and North, M.J., FEMS Microbiol. Lett., 96 (1992) 67.
Lustigman, S., Brotman, B., Huima, T., Prince, A.M. and McKerrow, J.H., J. Biol. Chem., 267 (1992) 17339.
Stoka, V., Nycander, M., Lenarcic, B., Labriola, C., Cazzulo, J.J., Björk, I. and Turk, V., FEBS Lett., 370 (1995) 101.
Serveau, C., Lalmanach, G., Juliano, M.A., Scharfstein, J., Juliano, L. and Gauthier, F., Biochem. J., 313 (1996) 951.
Taylor, M.A.J., Baker, K.C., Briggs, G.S., Connerton, I.F., Cummings, N.J., Pratt, K.A., Revell, D.F., Freedman, R.B. and Goodenough, P.W., Protein Eng., 8 (1995) 59.
Galvaoquintao, L., Alfieri, S.C., Ryter, A. and Rabinovitch, M., Parasitology, 101 (1990) 7.
Rabinovitch, M., Parasitol. Today, 5 (1989) 299.
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Robertson, C.D., Coombs, G.H., North, M.J. et al. Parasite cysteine proteinases. Perspectives in Drug Discovery and Design 6, 99–118 (1996). https://doi.org/10.1007/BF02174048
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DOI: https://doi.org/10.1007/BF02174048