Abstract
One goal of protein design and structural biochemistry is the reduction of complex molecules to small functional units that are amenable to high resolution analysis and rapid modification. We have developed a variety of small molecules which biochemically and biologically mimic the combining sites of proteins of the immunoglobulin superfamily. The chemical and biological properties of peptide mimetics suggest that these analogs can be used as indicators for new pharmaceutical agents. Mimetics are powerful tools for the study of molecular recognition since they are small in size, maintain solubility in physiologic fluids and are amenable to detailed structural studies. As such, they represent a step toward the rational design of low molecular weight non–peptide pharmaceutical agents devoid of some of the shortcomings of conventional peptides. Here we discuss the rationale and approaches for the development of these molecules, and their current and future applications.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Marshall, G.R., Gorin, F.A. and Moore, M.L. Peptide conformation and biological activity. Ann. Rep. Med. Chem 13: 227–238.
Hruby, V.J., Al-Obeidi, F. and Kazmierski, W. 1990. Emerging approaches in the molecular design of receptor-selective peptide ligands: conformational, topographical and dynamic considerations. Biochem J. 268: 249–262.
Tobias, D.J., Sneddon, S.F. and Brooks, C.L. III. 1990. Reverse turns in blocked dipeptides are intrinsically unstable in water. J. Mol. Biol. 216: 783–796.
Mutter, M. 1988. Nature's rules and chemist's tools: a way for creating novel proteins. Trends Biochem. Sci. 13(7): 260–265.
Saragovi, H.U., Fitzpatrick, D., Raktabuhr, A., Nakanishi, H., Kahn, M. and Greene, M.I. 1991. Design and synthesis of a mimetic of an antibody complementarity region. Science 253: 792–795.
Chen, S., Chrusciel, R.A., Nakanishi, H., Raktabuhr, A., Sato, A., Weiner, D.B., Hoxie Saragovi, H.U., Greene, M.I. and Kahn, M. 1992. Design and synthesis of a β-turn mimetic that inhibit HIVgpl20 binding and infection of human lymphocytes. Proc. Natl. Acad. Sci. USA. In press.
Rose, G.D., Gierasch, L.M. and Smith, J.A. 1985. Turns in peptides and proteins. Adv. Protein Chem. 37: 1–109.
Bernstein, F.C., Koetzle, T.F., Williams, G.J.B., Meyer, E.F. Jr., Brice, M.D., Rodgers, J.R., Kennard, O., Shimanouchi, T. and Tasumi, M. 1977. The protein data bank: a computer-based archival file for macromolecular structures. J. Mol. Biol. 112: 535–542.
Sibanda, B.L., Blundell, T.L. and Thornton, J.M. Conformation of beta-hairpins in protein structures. A systematic classification with applications to modelling by homology, electron density fitting and protein engineering. 1989. J. Mol. Biol. 206: 759–777.
Martin, A.C.R., Cheetham, C. and Rees, A.R. 1989. Modeling antibody hypervariable loops: a combined algorithm. Proc. Natl. Acad. Sci. USA 86: 9268–9272.
Williams, W.V., Guy, R.H., Rubin, D.H., Robey, F., Myers, J.N., Richer-Emmons, T., Weiner, D.B. and Greene, M.I. Sequences of the cell-attachment sites of the reovirus type 3 and its anti-idiotypic/anti-receptor antibody: modeling of their three dimensional structures. Proc. Natl. Acad. Sci. USA 85: 6488–6490.
Williams, W.V., Emmons, T., Weiner, D.B., Rubin, D.H. and Greene, M.I. 1991. Contact residues and predicted structures of the reovirus type 3-receptor interaction. J. Biol. Chem. 266: 9241–9250.
Williams, W.V., Moss, D.A., Kieber-Emmons, T., Cohen, J.A., Myers, J.N., Weiner, D.B. and Greene, M.I. 1989. Development of biologically active peptides based on antibody structure. Proc. Natl. Acad. Sci. USA 86: 5537–5541.
Taub, R., Gould, R.J., Ciccarone, T.M., Hoxie Friedman, P.A., Shattil, S.J. and Garsky, V.M. 1989. A monoclonal antibody against the platelet fibrinogen receptor contains a sequence that mimics a receptor recognition domain in fibrinogen. J. Biol. Chem. 264: 259–265.
Weiner, D.B., Williams, W.V., Merva, M.J., Berzofsky, J.A. and Greene, M.I. 1990. In: Vaccines, 339–345. Cold Spring Harbor Press, NY.
Capon, D.J., Chamow, S.M., Mordenti, J., Marstrs, S.A., Gregory, T., Mitsuya, H., Byrn, R.A., Lucas, C., Wurm, F.M. and Groopman, J.E. 1989. Designing CD4 immunoadhesins for AIDS therapy. Nature 337: 525–531.
Ishida, T., Yoneda, S., Doi, M., Inoue, M. and Kitamura, K. 1988. Molecular dynamics simulations of (Met5)-and (D-Ala2, Met5)-enkephalins. Biological implications of monomeric folded and dimeric unfolded conformations. Biochem. J. 255: 621–628.
Smith, G.D. and Griffin, J.F. 1978. Conformation of [Leu5]Enkephalin from X-ray diffraction: features important for recognition at opiate receptor. Science 199: 1214–1216.
Bugg, C.E., Ealick, S.E., Montgomery, J.A., Secrist, J.A., Babu, Y.S., Erion, M.D. and Gulda, W.C. 1992. In: Techniques in Protein Chemistry III. Angelets, R. (Ed.). The Protein Society Academic Press, NY.
Knighton, D.R., Zheng, G.H., Ten Eyck, L.E., Ashford, V.A., Xuong, N.H., Taylor, S.S. and Sowadski, J.M. 1991. Crystal structure of the catalytic subunit of cylcic adenosine monophosphate-dependent protein kinase. Science 253: 407–414.
Knighton, D.R., Zheng, G.H., Ten Eyck, L.F., Xuong, N.H., Taylor, S.S. and Sowadski, J.M. 1991. Structure of a peptide inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science 253: 414–420.
Bowie, J.U. and Sauer, R.T. 1989. Identifying determinants of folding and activity for a protein of unknown structure. Proc. Natl. Acad. Sci. USA 86: 2152–2156.
Zurawski, S.M., Imler, J.L. and Zurawski, G. 1990. Partial agonist/antagonist mouse interleukin-2 proteins indicate that a third component of the receptor complex functions in signal transduction. EMBO J. 9: 3899–3905.
Evans, B.E., Bock, M.G., Rittle, K.E., DiPardo, R.M., Whitter, W.L., Veber, D.F., Anderson, P.S. and Freidinger, R.M. 1986. Design of potent, orally effective, nonpeptidal antagonists of the peptide hormone cholecystoki-nin. Proc. Natl. Acad. Sci. USA 83: 4918–4922.
Lam, K.S., Salmon, S.E., Hersh, E.M., Hruby, V.J., Kazmierski, W.M. and Knapp, R.J. 1991. A new type of synthetic peptide library for identifying ligand binding activity. Nature 354: 82–84.
Houghten, R.A., Pinilla, C., Blondelle, S.E., Appel, J.R., Dooley, C.T. and Cuervo, J.H. 1991. Generation and use of synthetic peptide combinatorial libraries for basic research and drug discovery. Nature 354: 84–86.
Fodor, S.P., Read, J.C., Pirrung, M.C., Stryer, L., Lu, A.T. and Solas, D. 1991. Light-directed, spatially addressable parallel chemical synthesis. Science 251: 767–773.
Scott, J.K. and Smith, G.P. 1990. Searching for peptide ligands with an epitope library. Science 249: 386–390.
Cwirla, S.E., Peters, E.A., Barrett, R.W. and Dower, W.J. 1990. Peptides on phage, a vast library of perptides for identifying ligands. Proc. Natl. Acad. Sci. USA 87: 6387–6382.
Devlin, J.J., Panganiban, L.C. and Devlin, P.E. 1990. Random peptide libraries: a source of specific protein binding molecules. Science 249: 404–406.
Finberg, R.W., Diamond, D.C., Mitchell, D.B., Rosenstein, Y., Soman, G., Norman, T.C., Schreiber, S.L. and Burakoff, S.J. 1990. Prevention of HIV I infection and preservation of CD4 function by the binding of CPFs to gp120. Science 249: 287–291.
Williams, W.V., Weiner, D.B., Kieber-Emmons, T. and Greene, M.I. 1990. Antibody geometry and form: three-dimensional relationships between anti-idiotypic antibodies and external antigens. Trends in Biotechnology 8: 256–263.
Kieber Emmons, T. and Kohler, H. 1986. Towards a unified theory of immunoglobulin structure function relations. Immunol. Rev. 90: 29–48.
Kieber-Emmons, T., Williams, W.V. and Greene, M.I. 1991. Anti receptor antibody structure and peptide design, p. 53–63. Monoclonal Antibodies: Applications in Clinical Oncology. A. Epenetos (Ed.) Chapman and Hall Medical Publishers, UK.
Williams, A.F. 1987. A year in the life of the immunoglobulin superfamily. Immunology Today. 8: 298–303.
Eisenberg, D., Wilcox, W., Eshita, S.M., Pryciak, P.M., Peng Ho, S. and deGrado, W.F. 1986. The design, synthesis, and crystallization of an alpha-helical peptide. Proteins 1: 16–22.
Anthony-Cahill, S.J., Benfield, P.A., Fairman, R., Wasserman, Z.R., Brenner, S.L., Stafford, W.F. III, Altenbach, C., Hubbell, W.L. and deGrado, W.F. 1992. Molecular characterisation of helix-loop-helix peptides. Science 255: 79–83.
Karle, I.L., Flippen Anderson, J.L., Sukumar, M. and Balaram, P. 1992. Helix packing of leucine-rich peptides: a parallel leucine ladder in the structure of Boc-Aib-Leu-Aib-I. eu-Leu-Leu-Aib-Leu-Aib-Ome. Proteins 12: 324–330.
Becker, T., Weber, K. and Johnsson, N. 1990. Protein protein recognition via short amphiphilic helices; a mutational analysis of the binding site of annexin II for p11. EMBO J. 9: 4207–4213.
deVos, A.M., Ultsch, M. and Kossiakoff, A.A. 1992. Human growth hormone and extracelular domain of its receptor: crystal structure of the complex. Science 255: 306–312.
Waldmann, T.A. 1991. Monoclonal antibodies in diagnosis and therapy. Science 252: 1657–1662.
Watanabe, M., Chen, Z.W., Tsubota, H., Lord, C.I., Levine, C.G. and Letvin, N.L. 1991. Soluble human CD4 elicits an antibody response in rhesus monkeys that inhibits simian immunodeficiency virus replication. Proc. Natl. Acad. Sci. USA 88: 120–124.
Olson, G.L., Voss, M.E., Hill, D.E., Kahn, M., Madison, V.S. and Cook, C.M. 1990. Design and synthesis of a protein beta turn mimetic. Jour. Am. Chem. Soc. 112: 323–333.
Kahn, M., Wilke, S., Chen, B., Fujita, K., Lee, Y.H. and Johnson, M.E. 1988. The design and synthesis of mimetics of peptide beta-turns. J. Mol. Recognition 1: 75–79.
Ball, J.B. and Alewood, P.F. 1990. Conformational constraints: nonpeptide beta-turn mimics. J. Mol. Recognition. 3: 55–64.
Williams, A.F. and Barclay, A.N. 1988. The immunoglobulin superfamily -domains for cell surface recognition. Annual Review of Immunol. 6: 381–405.
Ryu, S.E., Kwong, P.D., Truneh, A., Porter, T.B., Arthos. J., Rosenberg, M., Dai, X.P., Xuong, N.H., Axel, R., Sweet, R.W. and Hendrikson, M. 1990. Crystal structure of an HIV-binding recombinant fragment of human CD4. Nature 348: 419–426.
Brodsky, M.H., Warton, M., Myers, R.M. and Littman, D.R. 1990. Analysis of the site in CD4 that binds to the HIV envelope glycoprotein. J. Immunol. 144: 3078–3086.
IveyHoyle, M., Culp, J.S., Chaikin, M.A., Hellmig, B.D., Matthews, T.J., Sweet, R.W. and Rosenberg, M. 1991. Envelope glycoproteins from biologically active diverse isolates of immunodeficiency viruses have widely different affinities for CD4. Proc. Natl. Acad. Sci. USA 88: 512–516.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Saragovi, H., Greene, M., Chrusciel, R. et al. Loops and Secondary Structure Mimetics: Development and Applications in Basic Science and Rational Drug Design. Nat Biotechnol 10, 773–778 (1992). https://doi.org/10.1038/nbt0792-773
Issue Date:
DOI: https://doi.org/10.1038/nbt0792-773