Summary
Peptide substrates of HIV-1 protease can be divided into two categories based on the nature of the scissile dipeptide and amino acid preference at the S2 and S2' subsites. Inhibitors based on substrate peptide sequences seem to fall into two similar categories as well. There has been tremendous progress in the design of inhibitors for the HIV protease since the first peptide-based inhibitors were described in 1989. Using a variety of different dipeptide isosteres, it has been possible to obtain highly potent, highly selective inhibitors of HIV protease which have Ki values in the subnanomolar range and which exhibit anti-infective activity in vitro in the nanomolar range. Protease inhibitors developed by Roche, Abbott, Searle and Dupont-Merck are currently undergoing clinical trials. The rapid progress in this field, the diversity of inhibitor types and the increasing use of structural information in designing nonpeptide inhibitors augurs well for future success of protease inhibitor-based therapy.
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References
Debouck, C., Deckman, I.C., Grant, S.K., Craig, R.J. and Moore, M.L., In Pearl, L.H. (Ed.) Retroviral Proteases: Control of Maturation and Morphogenesis, Stockton Press, New York, 1990, pp. 9–17.
Huff, J.R., J. Med. Chem. 34 (1991) 2305.
Martin, J.A., Antiviral Res., 17 (1992) 265.
Meek, T.D., J. Enzyme Inhib., 6 (1992) 65.
Pearl, L.H. and Taylor, W.R., Nature, 329 (1987) 351.
Meek, T.D., Dayton, B.D., Metcalf, B.W., Dreyer, G.B., Strickler, J.E., Gorniak, J.G., Rosenberg, M., Moore, M.L., Magaard, V.W. and Debouck, C., Proc. Natl. Acad. Sci. USA, 86 (1989) 1841.
Seelmeier, S., Schmidt, H., Turk, V. and Von der Helm, K., Proc. Natl. Acad. Sci. USA, 85 (1988) 6612.
Suguna, K., Padlan, E.A., Smith, C.W., Carlson, W.D. and Davies, D., Proc. Natl. Acad. Sci. USA, 84 (1987) 7009.
Greenlee, W.J., Med. Res. Rev., 10 (1990) 173.
Clavel, F., Guyader, M., Guetard, D., Salle, M., Montagnier, L. and Alizon, M., Nature, 324 (1986) 691.
Guyader, M., Emerman, M., Sonigo, P., Clavel, F., Montagnier, L. and Alizon, M., Nature, 326 (1987) 662.
Tözsér, J., Bláha, I., Copeland, T.D., Wondrak, E.M. and Oroszlan, S., FEBS Lett., 281 (1991) 77.
Poorman, R.A., Tomasselli, A.G., Heinrikson, R.L. and Kézdy, F.J., J. Biol. Chem., 266 (1991) 14544.
Tomasselli, A.G., Hui, J.O., Sawyer, T.K., Staples, D.J., Bannow, C., Reardon, I.M., Howe, W.J., DeCamp, D.L., Craik, C.S. and Heinrikson, R.L., J. Biol. Chem., 265 (1990) 14675.
Tözsér, J., Gutschina, A., Weber, I.T., Bláha, I., Wondrak, E.M. and Oroszlan, S., FEBS Lett., 279 (1991) 356.
Abeles, R.H., Drug. Dev. Res., 10 (1987) 221.
Bartlett, P.A. and Marlowe, C.K., Biochemistry, 22 (1983) 4618.
Bartlett, P.A. and Marlowe, C.K., Biochemistry 26 (1987) 8553.
Imperiale, B. and Abeles, R.H., Biochemistry, 25 (1986) 3760.
Mookhtiar, K.A., Marlowe, C.K., Bartlett, P.A. and Wart, H.E.V., Biochemistry, 26 (1987) 1962.
Imperiale, B. and Abeles, R.H., Biochemistry, 26 (1987) 4474.
Schechter, I. and Berger, A., Biochem. Biophys. Res. Commun., 27 (1967) 157.
Henderson, L.E., Benveniste, R.E., Sowder, R., Copeland, T.D., Schultz, A.M. and Oroszlan, S., J. Virol., 62 (1988) 2587.
Pearl, L.H. and Taylor, W.R., Nature, 328 (1987) 482.
Pettit, S.C., Simsic, J., Loeb, D.D., Everitt, L., Hutchinson III, C.A.Q. and Swanstrom, R., J. Biol. Chem., 266 (1991) 14539.
Moore, M.L., Bryan, W.M., Fakhoury, S.A., Magaard, V.W., Huffman, W.F., Dayton, B.D., Meek, T.D., Hyland, L., Dreyer, G.B., Metcalf, B.M., Strickler, J.E., Gorniak, J.G. and Debouck, C., Biochem. Biophys. Res. Commun., 159 (1989) 420.
Darke, P.L., Nutt, R.F., Brady, S.F., Garsky, V.M., Ciccarone, T.M., Leu, C.-T., Lumma, P.K., Freidinger, R.M., Veber, D.F. and Sigal, I.S., Biochem. Biophys. Res. Commun., 156 (1988) 297.
Kotler, M., Danho, W., Katz, R.A., Leis, J. and Skalka, A.M., J. Biol. Chem., 264 (1989) 3428.
Richards, A.D., Phylip, L.H., Farmerie, W.G., Scarborough, P.E., Alvarez, A., Dunn, B.M., Hirel, P.-H., Konvalinka, J., Strop, P., Pavlickova, L., Kostka, V. and Kay, J., J. Biol. Chem., 265 (1990) 7733.
Dreyer, G.B., Boehm, J.C., Chenera, B., DesJarlais, R.L., Hassell, A.M., Meek, T.D., Tomaszek Jr., T.A. and Lewis, M., Biochemistry, 32 (1993) 937.
Tropea, J.E., Nashed, N.T., Louis, J.M., Sayer, J.M. and Jerina, D.M., Bioorg. Chem., 20 (1992) 67.
Billich, A., Hammerschmid, F. and Winkler, G., Biol. Chem. Hoppe-Seyler, 371 (1990) 265.
Krausslich, H.-G., Ingraham, R.H., Skoog, M.T., Wimmer, E., Pallai, P.V. and Carter, C.A., Proc. Natl. Acad. Sci. USA, 86 (1989) 807.
Kotler, M., Katz, R.A., Danho, W., Leis, J. and Skalka, A.M., Proc. Natl. Acad. Sci. USA, 85 (1988) 4185.
Schneider, J. and Kent, S.B.H., Cell, 54 (1988) 363.
Debouck, C., In Dunn, B.M. (Ed.) Structure and Function of the Aspartic Proteinases: Genetics, Structures and Mechanisms, Vol. 306, Plenum Press, New York, 1991, pp. 407–415.
Tritsch, R.J., Cheng, Y.-S.E., Yin, F.H. and Erickson-Viitanen, S., J. Virol., 65 (1991) 922.
Tözsér, J., Weber, I.T., Gutschina, A., Bláha, I., Copeland, T.D., Louis, J.M. and Oroszlan, S., Biochemistry, 31 (1992) 4793.
Partin, K., Krausslich, H.-G., Ehrlich, L., Wimmer, E. and Carter, C., J. Virol., 64 (1990) 3938.
Hui, J.O., Tomasselli, A.G., Zürcher-Neely, H.A. and Heinrikson, R.L., J. Biol. Chem., 265 (1990) 21386.
Tomaszek Jr., T.A., Moore, M.L., Strickler, J.E., Sanchez, R.L., Dixon, S., Metcalf, B.W., Hassell, A., Dreyer, G.B., Brooks, I., Debouck, C., Meek, T.D. and Lewis, M., Biochemistry, 31 (1992) 10153.
Billich, A. and Winkler, G., Arch. Biochem. Biophys., 290 (1991) 186.
Jupp, R.A., Richards, A.D., Phylip, L.H., Kay, J., Konvalinka, J., Strop, P., Kostka, V., Scarborough, P.E., Farmerie, W.G. and Dunn, B.M., In Dunn, B.M. (Ed.) Structure and Function of the Aspartic Proteinases: Genetics, Structures and Mechanisms, Vol. 306, Plenum Press, New York, 1991, pp. 461–467.
Griffiths, J.T., Phylip, L.H., Konvalinka, J., Strop, P., Gustchina, A., Wlodawer, A., Davenport, R.J., Briggs, R., Dunn, B. and Kay, J., Biochemistry, 31 (1992) 5193.
Margolin, N., Heath, W., Osborne, E., Lai, M. and Vlahos, C., Biochem. Biophys. Res. Commun., 167 (1990) 554.
Miller, M., Jaskólski, M., Rao, J.K.M., Leis, J. and Wlodawer, A., Nature, 337 (1989) 576.
Miller, M., Schneider, J., Sathyanarayana, B.K., Toth, M.V., Marshall, G.R., Clawson, L., Selk, L., Kent, S.B.H. and Wlodawer, A., Science, 246 (1989) 1149.
Lapotto, R., Blundell, T., Hemmings, A., Overington, J., Wilderspin, A., Wood, S., Merson, J.R., Whittle, P.J., Danley, D.E., Geoghegan, K.F., Hawrylik, S.J., Lee, S.E., Scheld, K.G. and Hobart, P.M., Nature, 342 (1989) 299.
Swain, A.L., Miller, M.M., Green, J., Rich, D.H., Schneider, J., Kent, S.B.H. and Wlodawer, A., Proc. Natl. Acad. Sci. USA, 87 (1990) 8805.
Dreyer, G.B., Lambert, D.M., Meek, T.D., Carr, T.J., Tomaszek Jr., T.A., Fernandez, A.V., Bartus, H., Cacciavillani, E., Hassell, A.M., Minnich, M.S.R., Petteway, J., Metcalf, B.W. and Lewis, M., Biochemistry, 31 (1992) 6646.
Umezawa, H., Aoyagi, T., Morishima, H., Matzusaki, M., Hamada, H. and Takeuchi, T., J. Antibiot., 23 (1970) 259.
Marshall, G.R., Fed. Proc., Fed. Am. Soc. Exp. Biol., 35 (1976) 2494.
Marciniszyn, J.J., Hartsuck, J.A. and Tang, J., J. Biol. Chem., 251 (1976) 7088.
Aoyagi, T., In Umezawa, H., Takita, T. and Shiba, T., (Eds.) Bioactive Peptides Produces by Microorganisms, Halsted Press, New York, 1978, pp. 129–151.
Dreyer, G.B., Metcalf, B.W., Tomaszek Jr., T.A., Carr, T.J., Chandler III, A.C., Hyland, L., Moore, M.L., Strickler, J.E., Debouck, C. and Meek, T.D., Proc. Natl. Acad. Sci. USA, 86 (1989) 9752.
Richards, A.D., Roberts, R.F., Dunn, B.M., Graves, M.C. and Kay, J., FEBS Lett., 247 (1989) 113.
Cooper, J.B., Foundling, S.I., Blundell, T.L., Boger, J., Jupp, R.A. and Kay, J., Biochemistry, 28 (1989) 8596.
Bott, R., Subramanian, E. and Davies, D.R., Biochemistry, 21 (1982) 6956.
Fitzgerald, P.M.D., McKeever, B.M., VanMiddlesworth, J.F., Springer, J.P., Heimbach, J.C., Leu, C.-T., Herber, W.K., Dixon, R.A.F. and Darke, P.L., J. Biol. Chem., 265 (1990) 14209.
Raju, B. and Deshpande, M.S., Biochem. Biophys. Res. Commun., 180 (1991) 187.
Cooper, J., Foundling, S., Hemmings, A. and Blundell, T., Eur. J. Biochem., 169 (1987) 215.
Urban, J., Konvalinka, J., Stehlíkova, J., Gregorova, E., Majer, P., Soucek, M., Andreansky, M., Fabry, M. and Strop, P., FEBS Lett., 298 (1992) 9.
De Solms, S.J., Giuliani, E.A., Guare, J.P., Vacca, J.P., Sanders, W.M., Graham, S.L., Wiggins, J.M., Darke, P.L., Sigal, I.S., Zugay, J.A., Emini, E.A., Schlief, W.A., Quintero, J.C., Anderson, P.S. and Huff, J.R., J. Med. Chem., 34 (1991) 2852.
Vacca, J.P., Guare, J.P., De Solms, S.J., Sanders, W.M., Giuliani, E.A., Young, S.D., Darke, P.L., Zugay, J., Sigal, I.S., Schlief, W.A., Quintero, J.C., Emini, E.A., Anderson, P.S. and Huff, J.R., J. Med. Chem., 34 (1991) 1225.
Lyle, T.A., Wiscount, C.M., Guare, J.P., Thompson, W.J., Anderson, P.S., Darke, P.L., Zugay, J.A., Emini, E.A., Schlief, W.A., Quintero, J.C., Dixon, R.A.F., Sigal, I.S. and Huff, J.R., J. Med. Chem., 34 (1991) 1228.
Young, S.D., Payne, L.S., Thompson, W.J., Gaffin, N., Lyle, T.A., Britcher, S.F., Graham, S.L., Schultz, T.H., Deana, A.A., Darke, P.L., Zugay, J., Schlief, W.A., Quintero, J.C., Emini, E.A., Anderson, P.S. and Huff, J.R., J. Med. Chem. 35 (1992) 1702.
Thompson, W.J., Fitzgerald, P.M.D., Holloway, M.K., Emini, E.A., Darke, P.L., McKeever, B.M., Schlief, W.A., Quintero, J.C., Zugay, J.A., Tucker, T.J., Schwering, J.E., Homnick, C.F., Nunberg, J., Springer, J.P. and Huff, J.R., J. Med. Chem., 35 (1992) 1685.
Roberts, N.A., Martin, J.A., Kinchington, D., Broadhurst, A.V., Craig, J.C., Duncan, I.B., Galpin, S.A., Handa, B.K., Kay, J., Kröhn, A., Lambert, R.W., Merrett, J.H., Mills, J.S., Parkes, K.E.B., Redshaw, S., Ritchie, A.J., Taylor, D.L., Thomas, G.J. and Machin, P.J., Science, 248 (1990) 358.
Rich, D.H., Sun, C.-Q., Prasad, J.V.N., Pathiasseril, A., Toth, M.V., Marshall, G.R., Clare, M., Mueller, R.A. and Houseman, K., J. Med. Chem., 34 (1991) 1222.
Tam, T.F., Carrière, J., MacDonald, I.D., Sastelhano, A.L., Pliura, D.H., Dewdney, N.J., Thomas, E.M., Bach, C., Barnett, J., Chan, H. and Krantz, A., J. Med. Chem., 35 (1992) 1318.
Grobelny, D., Wondrak, E.M., Galardy, R.E. and Oroszlan, S., Biochem. Biophys. Res. Commun., 169 (1990) 1111.
Ikeda, S., Ashley, J.A., Wirshing, P. and Janda, K.D., J. Am. Chem. Soc., 114 (1992) 7604.
Getman et al. recently described novel, potent hydroxyethylurea isosteres of the structure — NHCH(R)CH(OH)-CH2N(R′)CONHR″ which are analogous to hydroxyethylene isosteres. In this case, however, the Pl′ side chain is now attached to an sp2, nonchiral urea nitrogen rather than to an sp3 carbon atom. In contrast to hydroxyethylene inhibitors, these hydroxyethylurea inhibitors show a strong preference for the (R)-hydroxyl stereochemistry. X-ray crystal analysis of one such inhibitor bound to HIV-1 protease reveals a novel binding mode, however, with the Pl′ side chain R′ actually occupying the S2′ subsite and the P2′ side chain R″ occupying the Sl′ subsite. Getman, D.P., DeCrescenzo, G.A., Heintz, R.M., Reed, K.L., Talley, J.J., Bryant, M.L., Houseman, K.A., Marr, J.J., Mueller, R.A., Vazquez, M.L., Shieh, H.-S., Stallings, W.C. and Stegeman, R.A., J. Med. Chem., 36 (1993) 288.
Erickson, J., Neidhart, D.J., VanDrie, J., Kempf, D.J., Wang, X.C., Norbeck, D.W., Plattner, J.J., Rittenhouse, J.W., Turon, M., Wideburg, N., Kohlbrenner, W.E., Simmer, R., Helfrich, R., Paul, D.A. and Knigge, M., Science, 249 (1990) 527.
Bone, R., Vacca, J.P., Anderson, P.S. and Holloway, M.K., J. Am. Chem. Soc., 113 (1991) 9382.
Kempf, D.J., Norbeck, D.W., Codacovi, L., Wang, X.C., Kohlbrenner, W.E., Wideburg, N.E., Paul, D.A., Knigge, M.F., Vasavanonda, S., Craig-Kennard, A., Saldivar, A.W., Rosenbrook, J., Clement, J.J., Plattner, J.J. and Erickson, J., J. Med. Chem., 33 (1990) 2687.
Luly, J.R., BaMaung, N., Soderquist, J., Fung, A.K.L., Stein, H., Kleinert, H.D., Marcotte, P.A., Egan, D.A., Bopp, B., Merits, I., Bolis, G., Greer, J., Perun, T.J. and Plattner, J.J., J. Med. Chem., 31 (1988) 2264.
Hanson, G.J., Baran, J.S., Clare, M., Williams, K., Babler, M., Bittner, S.E., Russell, M.A., Papaioannou, S.E., Yang, P.-C. and Walsh, G.M., In Rivier, J.E. and Marshall, G.R. (Eds.) Peptides, Chemistry, Structure and Biology, Proceedings of the Eleventh American Peptide Symposium, ESCOM, Leiden, 1990, pp. 396–398.
Humber, D.C., Cammack, N., Coates, J.A.V., Cobley, K.N., Orr, D.C., Storer, R., Weingarten, G.G. and Weir, M.P., J. Med. Chem., 35 (1992) 3080.
Kahn, M., Nakanishi, H., Chrusciel, R.A., Fitzpatrick, D. and Johnson, M.E., J. Med. Chem., 34 (1991) 3395.
Toniolo, C., Valle, G., Crisma, M., Kaltenbronn, J.S., Repine, J.T., Van Binst, G., Elseviers, M. and Tourwe, D., Pept. Res., 2 (1989) 332.
Dauber-Osguthorpe, P., Jones, D.K., Campbell, M.M., Semple, G. and Osguthorpe, D.J., Tetrahedron Lett., 31 (1990) 917.
Huffman, W.F., Callahan, J.F., Eggleston, D.S., Newlander, K.A., Takata, D.T., Codd, E.E., Walker, R.F., Schiller, P.W., Lemieux, C., Wire, W.S. and Burks, T.F., In Marshall, G.R. (Ed.) Peptides, Chemistry and Biology, Proceedings of the Tenth American Peptide Symposium, ESCOM, Leiden, 1988, pp. 105–108.
Huffman, W.F., In Wermuth, C.G., Koga, N., König, H. and Metcalf, B.W. (Eds.) Medicinal Chemistry for the 21st Century, Blackwell Scientific Publications, London, 1992, pp. 247–257.
Newlander, K.A., Callahan, J.F., Moore, M.L., Tomaszek Jr., T.A. and Huffman, W.F., J. Med. Chem., in press.
Moore, M.L., Fakhoury, S.A., Bryan, W.M., Bryan, H.G., Tomaszek Jr., T.A., Grant, S.K., Meek, T.D. and Huffman, W.F., In Smith, J.A. and Rivier, J.E. (Eds.) Peptides, Chemistry and Biology, Proceedings of the Twelfth American Peptide Symposium, ESCOM, Leiden, 1992, pp. 781–782.
Grant, S.K., Moore, M.L., Fakhoury, S.A., Tomaszek Jr., T.A. and Meek, T.D., Biorg. Med. Chem. Lett., 2 (1992) 1441.
Debouck, C. and Metcalf, B.W., Drug Dev. Res., 21 (1990) 1.
Krohn, A., Redshaw, S., Ritchie, J.C., Graves, B.J. and Hatada, M.H., J. Med. Chem., 34 (1991) 3340.
Kempf, D.J., Codacovi, L., Wang, X.C., Kohlbrenner, W.E., Wideburg, N.E., Saldivar, A., Vasavanonda, S., Marsh, K.C., Bryant, P., Sham, H.L., Green, B.E., Betebenner, D.A., Erickson, J. and Norbeck, D.W., J. Med. Chem., 36 (1993) 320.
Jacobsen, H., Craig, C.J., Duncan, I.B., Krohn, A., Mous, J. and Yasargil, K., J. Cell. Biol., Suppl. 17E (1993) 90.
Singh, M.K., Toyoshima, T., Markowitz, M., Kempf, D.J., Norbeck, D.W., Erickson, J. and Ho, D.D., J. Cell. Biol., Suppl. 17E (1993) 86.
Johnston, M.I. and Hoth, D.F., Science, 260 (1993) 1286.
Blair, E.D., Wood, A.J., Blance, C., Bains, S., Darby, G., Wilderspin, A. and Sugrue, R., J. Cell. Biol., Suppl. 17E (1993) 74.
Johnson, V.A., Merrill, D.P., Chou, T.-C. and Hirsch, M.S., J. Infect. Dis., 166 (1992) 1143.
Tomasselli, A.G., Olsen, M.K., Hui, J.O., Staples, D.J., Sawyer, T.K., Heinrikson, R.L. and Tomich, C.-S. C., Biochemistry, 29 (1990) 264.
Cushman, M., Oh, Y.-I., Copeland, T.D., Oroszlan, S. and Snyder, S.W., J. Org. Chem., 56 (1991) 4161.
Toth, M.V., Chiu, F., Glover, G., Kent, S.B.H., Ratner, L., Heyden, N.V., Green, J., Rich, D.H. and Marshall, G.R., In Rivier, J.E. and Marshall, G.R. (Eds.) Peptides, Chemistry, Structure and Biology, Proceedings of the Eleventh American Peptide Symposium, ESCOM, Leiden, 1990, pp. 835–838.
Tucker, T.J., Lumma Jr., W.C., Payne, L.S., Wai, J.M., De Solms, S.J., Guiliani, E.A., Darke, P.L., Heimbach, J.C., Zugay, J.A., Schlief, W.A., Quintero, J.C., Emini, E.A., Huff, J.R. and Anderson, P.S., J. Med. Chem., 35 (1992) 2525.
Mimoto, T., Imai, J., Tanaka, S., Hattore, N., Kisanuki, S., Akaji, K. and Kiso, Y., Chem. Pharm. Bull., 39 (1991) 3088.
Raju, B. and Deshpande, M.S., Biochem. Biophys. Res. Commun., 180 (1991) 181.
Wlodawer, A., Miller, M., Jaskólski, M., Sathyanarayana, B.K., Baldwin, E., Weber, I.T., Selk, L.M., Clawson, L., Schneider, J. and Kent, S.B.H., Science, 245 (1989) 616.
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Moore, M.L., Dreyer, G.B. Substrate-based inhibitors of HIV-1 protease. Perspectives in Drug Discovery and Design 1, 85–108 (1993). https://doi.org/10.1007/BF02171657
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DOI: https://doi.org/10.1007/BF02171657