Torrey Pines Institute for Molecular Studies science image
Torrey Pines Institute for
Molecular Studies
3550 General Atomics Court, 2-129
San Diego, CA 92121-1122
USA
Scientists
Clemencia Pinilla
Associate Member
Immunology

858.455.3783 - phone
858.455.3804 - fax

Exploring Immune Recognition using Combinatorial Approaches

An understanding of human B-cell and T-cell recognition is fundamental for the determination of the immune response mechanisms and their role in the prevention and cause of human disease. This understanding can be applied to the design of diagnostics and synthetic vaccines. In recent years, the understanding of B- and T-cell specificity has been advanced significantly by the development and use of combinatorial libraries made up of millions of synthetic peptides.

Improved Immunodiagnostics and Synthetic Vaccines

It is believed that the majority of antibodies recognize conformational regions of protein antigens, however, it has been shown that antibodies can crossreact with linear peptides of the protein. Peptides can therefore be used effectively to define antibody specificity. We have carried out extensive epitope mapping studies for a number of antigen-antibody interactions using individual peptide analogs and peptide combinatorial libraries [1]. In one example, we have identified peptides that inhibit an anti-carbohydrate antibody nearly 1,000-fold better than the original carbohydrate antigen [2].

It has become clearer that T-cell specificity is not as stringent as initially believed [3]. In collaboration with Dr. Roland Martin's group at the National Institute of Neurological Disorders and Stroke, we have studied the specificities of autoreactive and pathogen-specific T-cell clones using positional scanning combinatorial libraries. From these studies we have identified the native antigens as well as antigens that induce proliferative responses, at concentrations up to six orders of magnitude lower than the native ligand. This approach, when combined with biometric prediction algorithms, is being used to identify ligands for T-cell clones of unknown specificities derived from patients with Multiple Sclerosis and Lyme disease. In a recent paper [4], we identified multiple Borrelia burdorferi derived peptides and molecular mimics from human proteins recognized by a cerebrospinal fluid-derived T-cell clone of a patient suffering from chronic Lyme disease. These efforts will have direct applications toward the development of improved immunodiagnostics and synthetic vaccines.

We are also using combinatorial libraries to identify new estrogen receptor ligands with chemical characteristics that differ from estradiol. These novel compounds will enable further investigation and clarification of the cellular and molecular actions of estrogens and antiestrogens. Such compounds will also increase the understanding of estrogen antagonism, and may lead to the development of agents for use in endocrine therapy against breast cancer. Several new ligands have been identified and are undergoing further characterization studies.

Novel Antitumor Agents

Under the direction of TPIMS Senior Scientist Jon Appel, combinatorial libraries are being used to identify new compounds in a variety of biological systems in an effort to identify new antitumor agents. In collaboration with the National Cancer Institute, TPIMS' combinatorial libraries are tested against a diverse panel of 60 different human tumor cell lines. Recent studies have found several potent compounds that are undergoing further evaluation against solid tumors [5].

Deconvolution Strategies

The use of complex, but systematically arranged mixture-based combinatorial libraries has led to the identification of individual, biologically active compounds by the Institute and others [6]. We are also developing new deconvolution strategies that will facilitate the identification of active compounds from screening data that would otherwise be difficult or expensive to deconvolute using iterative or positional scanning approaches. These new methods are also being combined with the use of biometric algorithms.

Key References1-6

  1. Pinilla, C., et al. Exploring immunological specificity using synthetic peptide combinatorial libraries. Curr. Opin. Immunol. 11:193-202, 1999.
  2. Pinilla, C., et al. All-D peptides recognized by an anti-carbohydrate antibody identified from a positional scanning library. J. Mol. Biol. 283:1013-1025, 1998.
  3. Hemmer, B., et al. Probing degeneracy in T-cell recognition using peptide combinatorial libraries. Immunology Today 19:163-168, 1998.
  4. Hemmer, B., et al. Identification of candidate T cell epitopes and molecular mimics in chronic Lyme disease. Nature Medicine 5:1375-1382, 1999.
  5. Appel, J.R., et al. Identification of novel antitumor agents from mixture-based synthetic combinatorial libraries using cell-based assays. Molecular Diversity 4:91-102, 1999.
  6. Houghten, R.A., et al. Mixture-based synthetic combinatorial libraries. J. Med. Chem. 42:3743-3778, 1999.

Publications

  1. Greenbaum, J.A., Andersen, P.H., Blythe, M., Hui, H., Cachau, R.E., Crowe, J., Davies, M., Kolaskar, A.S., Lund, O., Morrison, S., Mumey, B., Ofran, Y., Pellequer, J., Pinilla, C., Ponomarenko, J.V., Raghava, G.P.S., van Regenmortel, M., Roggen, E.L., Sette, A., Schlessinger, A., Sollner, J., Zand, M. and Peters, B. Towards a consensus on datasets and evaluation metrics for developing B cell epitope prediction tools J.Mol.Recognition (20): 75-82, 2007.
  2. Karikari, C.A., Roy, I., Tyrggestad, E., Feldman, G., Pinilla, C., Welsh, K., Reed, J.C., Armour, E.P., Wong, J., Herman, J., Rakheja, D., and Maitra, A. Targeting the Apoptotic Machinery in Pancreatic Cancers using Small Molecule Antagonists of the X-linked Inhibitor of Apoptosis (XIAP) Protein. Mol Cancer Ther. 6(3):957-66, 2007.
  3. Lunemann, J.D., Gelderblom, H., Sospedra, M., Quandt, J.A., Pinilla, C., Marques, A., and Martin, R. CSF-Infiltrating T Cells Recognize Borrelial and CNS Auto-Antigens in Early Lyme Encephalitis. Infect Immun.75(1):243-51, 2007.
  4. Fujimoto, D., Pinilla, C., and Segall, A. New Peptide Inhibitors of Type IB Topoisomerases: Similarities and Differences Vis-a-vis Inhibitors of Tyrosine Recombinases J.Mol.Biol 363:891-907, 2006.
  5. Lustgarten, J., Dominguez, A.L., Pinilla, C. Identification of cross-reactive peptides using combinatorial libraries circumvents tolerance against Her-2/neu-immunodominant epitope. J. Immunol. 176:1796-1805, 2006.
  6. Nefzi, A., Hoesl, C.E., Pinilla, C., Kauffman, G.B., Maggiora, G.M., Pasquale, E., Houghten, R.A. Synthesis of platinum(II) chiral tetraamine coordination complexes J. Comb. Chem. 8:780-783, 2006.
  7. Sospedra, M., Muraro, P., Stefanova, I., Zhao, Y., Chung, K., Li, Y., Giulianotti, M., Simon, R., Mariuzza, R., Pinilla, C., Martin, R. Redundancy in antigen-presenting function of the HLA-DR and -DQ molecules in the multiple sclerosis-associated HLA-DR2 haplotype. J. Immunol. 36:1951-1961, 2006.
  8. Sospedra, M., Pinilla, C. The use of positional scanning synthetic peptide combinatorial libraries to identify immunological relevant peptides. chapter in Handbook of Biologically Active Peptides, 2006.
  9. Venturini, S., Allicotti, G., Zhao, Y., Simon, R., Burton, D., Pinilla, C., Poignard, P. Cross-reactivity of a human HIV-1-gag specific CD4+ T cell clone. Eur. J. Immunol. 36:27-36, 2006.
  10. Berezovskaya, O., Schimmer, A.D., Blinskii, A.B., Pinilla, C., Hoffman, R.M., Reed, J.C., Glinsky, G.V. Increased expression of apoptosis inhibitor protein XIAP contributes to anoikis resistance of circulating human prostate cancer metastasis precursor cells. Cancer Res. 65:2378-2386, 2005.
  11. Blondelle, S.E., Moya, R., Pinilla, C., Bihl, F., Brander, C., Boggiano, C. Highly immunogenic and broadly recognized HIV derived CTL epitope mimics. in press, In Bridges Between Disciplines, Proceedings of the 3rd Intl./28th Eur. Peptide Symposium, March 2005.
  12. Boggiano, C., Moya, R., Pinilla, C., Bihl, F., Brander, C., Sidney, J., Sette, A., Blondelle, S.E. Discovery and characterization of highly immunogenic and broadly recognized mimics of the HIV-1 CTL epitope Gag(77-85). Eur. J. Immunol. 35:1428-1437, 2005.
  13. Carter, B., Gronda, M., Wang, Z., Welsh, K., Pinilla, C., Andreeff, M., Schober, W., Nefzi, A., Pond, G., Mawji, I., Houghten, R., Ostresh, J., Brandwein, J., Minden, M., Schuh, A., Wells, R., Messner, H., Chun, K., Reed, J. Schimmer, A. Small-molecule XIAP inhibitors depress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells. Blood 105:4043-4050, 2005.
  14. Huseby, E.D., White, J., Crawford, F. Vass, T., Crawford, F., Becker, D., Pinilla, C., Marrack, P., Kappler, J.W. How the T cell repertoire becomes peptide and MHC specific. Cell 122:247-260, 2005.
  15. Kater, A.P., Dicker, F., Mangiola, M., Welsh, K., Houghten, R., Ostresh, J., Nefzi, A., Reed, J.C., Pinilla, C., Kipps, T.J. Inhibitors of XIAP sensitize CD40-activated chronic lymphocytic leukemia cells to CD95-mediated apoptosis. Blood 106:1742-1748, 2005.
  16. Markovic-Plese, S., Hemmer, B., Zhao, Y., Simon, R., Pinilla, C., Martin, R. High level of cross-reactivity in influenza virus hemagglutinin-specific CD4+ T-cell response: implications for the initiation of autoimmune response in multiple sclerosis. J. Neuroimmunol. 169:31-38, 2005.
  17. Sospedra, M., Zhao, Y., zur Hausen, H., Muraro, P., Hamashin, C., de Villiers, E., Pinilla, C., Martin, R. Recognition of conserved amino acid motifs of common viruses and its role in autoimmunity. PLoS.Pathog. 1:e41, 2005.
  18. Boldt, J.L., Pinilla, C., Segal, A. Reversible inhibitors of 1 integrase-mediated recombination efficiently trap Holliday junction intermediates and form the basis of a novel assay for junction resolution. J. Biol. Chem. 279:3472-3483, 2004.
  19. Judkowski, V., Pinilla, C., Alicotti, G., Flodstrom, M., Sanna, P., Sarvetnick, N. Strong attraction may be dangerous: parameters for the development of long term commitment. Mol. Immunol. 40:1109-1112, 2004.
  20. Judkowski, V., Rodriguez, E., Pinilla, C., Masteller, E., Bluestone, J.A., Sarvetnick, N., Wilson, D.B. Peptide specific amelioration of T cell mediated pathogenesis in murine type 1 diabetes. Clin. Immunol. 113:29-37, 2004.
  21. Judkowski, V.A., Allicotti, G.M., Sarvetnick, N., Pinilla, C. Peptides from common viral and bacterial pathogens can efficiently activate diabetogenic T-cells. Diabetes 53:2301-2309, 2004.
  22. Markovic-Plese, S., Pinilla, C., Martin, R. The initiation of the autoimmune response in multiple sclerosis. Clin. Neurol. Neurosurg. 106:218-222, 2004.
  23. Nino-Vasquez, J.J., Allicotti, G., Borras, E., Wilson, D.B., Valmori, D., Simon, R., Martin, R., Pinilla, C. A powerful combination: the use of positional scanning libraries and biometrical analysis to identify cross-reactive T cell epitopes. Mol. Immunol. 40:1063-1074, 2004.
  24. Schimmer, A.D., Welsh, K., Pinilla, C., Wang, Z., Krajewska, M., Bonneau, M.-J., Pedersen, I.M., Kitada, S., Scott, F.L., Bailly-Maitre, B., Glinsky, G., Scudiero, D., Sausville, E., Salvesen, G., Nefzi, A., Ostresh, J.M., Houghten, R.A., Reed, J.C. Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity. Cancer Cell 5:25-35, 2004.
  25. Shukaliak, Quandt J., Borras, E., Prat, E., Gelderblom, H., Houghten, R.A., Kashani, A., Pinilla, C., Stuerzebecher, C.S., Martin, R. Peptidic complex mixtures as therapeutic agents in CNS autoimmunity. Mol. Immunol. 40:1075-1087, 2004.
  26. Wang, Z., Cuddy, M., Samuel, T., Welsh, K., Schimmer, A., Hanaii, F., Houghten, R., Pinilla, C., Reed, J.C. Cellular, biochemical, and genetic analysis of mechanism of small molecule IAP inhibitors. J. Biol. Chem. 279:48168-48176, 2004.
  27. Wilson, D.B., Wilson, D.H., Schroder, K., Pinilla, C., Blondelle, S., Houghten, R.A., Garcia, K.C. Specificity and degeneracy of T cells. Mol. Immunol. 40:1047-1055, 2004
  28. Allicotti, G. Borras, E., Pinilla, C. A time-resolved fluorescence immunoassay (DELFIA) increases the sensitivity of antigen-driven cytokine detection. J. Immunoassay Immunochem. 24:345-358, 2003.
  29. Blondelle, S.E., Pinilla, C., Boggiano, C. Synthetic combinatorial libraries as an alternative strategy for the development of novel treatments for infectious diseases. Methods in Enzymology 369:322-344, 2003.
  30. Boggiano, C., Reixach, N., Pinilla, C., Blondelle, S.E. Successful identification of novel agents to control infectious diseases from screening mixture-based peptide combinatorial libraries in complex cell-based bioassays. Biopolymers (Pept. Sci.) 71:103-116, 2003.
  31. Hamashin, C., Spindler, L., Russell, S., Schink, A., Lambkin, I., O'Mahony, D., Houghten, R., Pinilla, C. Identification of novel small-molecule Ulex europaeus I mimetics for targeted drug delivery. Bioorg. Med. Chem. 11:4991-4997, 2003.
  32. Lambkin, I., Pinilla, C., Hamashin, C., Spindler, L., Russell, S., Schink, A., Moya-Castro, R., Allicotti, G., Higgins, L., Smith, M., Dee, J., Wilson, C., Houghten, R., O'Mahony, D. Toward targeted oral vaccine delivery systems: selection of lectin mimetics from combinatorial libraries. Pharm. Res. 20:1258-1266, 2003.
  33. Pinilla, C., Appel, J.R., Borras, E., Houghten, R.A. Advances in the use of synthetic combinatorial chemistry: Mixture-based libraries. Nat. Med. 9:118-122, 2003.
  34. Sospedra, M., Pinilla, C., Martin, R. Use of combinatorial peptide libraries for T-cell epitope mapping. Methods 29:236-247, 2003.
  35. You, S., Chen, C. , Lee, W.H., Wu, C.H., Judkowski, V., Pinilla, C., Wilson, D.B., Liu, C.P. Detection and characterization of T cells specific for BDC2.5 T cell-stimulating peptides. J. Immunol. 170:4011-4020, 2003.
  36. Zhao, Y., Pinilla, C., Valmori, D., Martin, R., Simon, R. Application of support vector machines for T-cell epitopes prediction. Bioinformatics 19: 1978-1984, 2003.
  37. Borras, E., Martin, R., Judkowski, V., Shukaliak, J., Zhao, Y., Rubio-Godoy, V., Valmori, D., Wilson, D., Simon, R., Houghten, R., Pinilla, C. Findings on T cell specificity revealed by synthetic combinatorial libraries. J. Immunol. Methods 267:79-97, 2002.
  38. Dutoit, V., Rubio-Godoy, V., Pittet, M.J., Zippelius, A., Dietrich, P.Y., Legal, F.A., Guillaume, P., Romero, P., Cerottini, J.C., Houghten, R.A., Pinilla, C., Valmori, D. Degeneracy of antigen recognition as the molecular basis for the high frequency of naive A2/Melan-a peptide multimer+ CD8+ T cells in humans. J. Exp. Med. 196:207-216, 2002.
  39. Lambkin, I., Pinilla, C. Targeting approaches to oral drug delivery. Expert Opin. Biol. Ther. 2:67-73, 2002.
  40. Pinilla, C., Giulianotti, M., Houghten, R. How to screen trillions of drug candidate compounds SP2 June:36-37, 2002.
  41. Pinilla, C., Giulianotti, M., Houghten, R. Mixed libraries speed up HTS even further SP2 August:18-19, 2002.
  42. Rubio-Godoy, V., Ayyoub, M., Dutoit, V., Servis, C., Schink, A., Rimoldi, D., Romero, P., Cerottini, J.-C., Simon, R., Zhao, Y., Houghten, R.A., Pinilla, C., Valmori, D. Combinatorial peptide library based identification of peptide ligands for tumor-reactive cytolytic T lymphocytes of unknown specificity. Eur. J. Immunol. 32: 2292-2299, 2002.
  43. Rubio-Godoy, V., Dutoit, V., Zhao, Y., Simon, R., Guillaume, P., Houghten, R.A., Romero, P., Cerottini, J.C., Pinilla, C., Valmori, D. Positional scanning-synthetic peptide library-based analysis of self- and pathogen-derived peptide coss-reactivity with tumor-reactive Melan-A-specific CTL. J. Immunol. 169:5696-5707, 2002.
  44. Rubio-Godoy, V., Pinilla, C., Dutoit, V., Borras, E., Simon, R., Zhao, Y., Cerottini, J.-C., Romero, P., Houghten, R.A., Valmori, D. Toward synthetic combinatorial peptide libraries in positional scanning format PS-SCL based identification of CD8+ tumor reactive T cell ligands: a comparative analysis of PS-SCL recognition by a single tumor-reactive CD8+ CTL clone. Cancer Research, 62:2058-2063, 2002.
  45. Boggiano, C., Pinilla, C., Walker, B.D., Blondelle, S.E. Identification and optimization of HIV-specific CTL antigens for vaccine design. In: Peptides: The Wave of the Future. Proceedings of the 2nd International/17th American Peptide Symposium. (Houghten, R.A., Lebl, M., Eds.), Kluwer Academic Publishers, Dordrecht, pp. 1023-1024, 2001.
  46. Borras, E., Gran, B., Martin, R., Pinilla, C. Characterization of highly stimulatory T cell ligands identified using positional scanning combinatorial libraries. In: Peptides: The Wave of the Future. Proceedings of the 2nd International/17th American Peptide Symposium. (Houghten, R.A., Lebl, M., Eds.), Kluwer Academic Publishers, Dordrecht, pp. 1051-1052, 2001.
  47. Judkowski, V., Pinilla, C., Schroder, K., Tucker, L., Sarvetnick, N., Wilson, D.B.  Identification of MHC class II-restricted peptide ligands, including a glutamic acid decarboxylase 65 sequence, that stimulate diabetogenic T cells from transgenic BDC2.5 nonobese diabetic mice. J. Immunol. 166:908-917, 2001.
  48. La Rosa, C., Krishnan, R., Markel, S., Schneck, J.P., Houghten, R.A., Pinilla, C., Diamond, D.J. Enhanced immune activity of cytotoxic T-lymphocyte epitope analogs derived from positional scanning synthetic combinatorial libraries. Blood 97:1776-1786, 2001.
  49. Martin, R., Gran, B., Zhao, Y., Markovic-Plese, S., Bielekova, B., Marques, A., Sung, M., Hemmer, B., Simon, R., McFarland, H.F., Pinilla, C. Molecular mimicry and antigen-specific T cell responses in multiple sclerosis and chronic CNS lyme disease. J. Autoimmunity 16:187-192, 2001.
  50. Pinilla, C., Appel, J.R., Houghten, R.A. Identification of B cell and T cell epitopes using synthetic peptide combinatorial libraries. In: Current Protocols in Immunology (J.E. Coligan, A.M. Krusibeek, D.H. Margulies, E.M. Shevach, and W. Strober, Eds.) John Wiley & Sons, Inc., New York. pp. 9.5.1-9.5.13, 2001.
  51. Pinilla, C., Borras, E., Martin, R., Zhao, Y., Simon, R. The integration of positional scanning libraries with bioinformatics and proteomics. In: Peptides: The Wave of the Future. Proceedings of the 2nd International/17th American Peptide Symposium. (Houghten, R.A., Lebl, M., Eds.), Kluwer Academic Publishers, Dordrecht, pp. 194-195, 2001.
  52. Pinilla, C., Rubio-Godoy, V., Dutoit, V., Guillaume, P., Simon, R., Zhao, Y., Houghten, R., Cerottini, J., Romero, P., Valmori, D. Combinatorial peptide libraries as an alternative approach to the identification of ligands for tumor reactive cytolytic T. lymphocytes. Cancer Research, 61:5153-5160, 2001.
  53. Zhao, Y., Gran, B., Pinilla, C., Markovic-Plese, S., Hemmer, B., Tzou, A., Whitney, L.W., Biddison, W.E., Martin, R., Simon, R. Combinatorial peptide libraries and biometric score matrices permit the quantitative analysis of specific and degenerate interactions between clonotypic T-cell receptors and MHC-peptide ligands. J. Immunol. 167:2130-2141, 2001.
  54. Cassell, G., Klemm, M., Pinilla, C., Segall, A. Dissection of bacteriophage λ site-specific recombination using synthetic peptide combinatorial libraries. J. Molecular Biology, 299:1193-1202, 2000.
  55. Hemmer, B., Kondo, T., Gran, B., Pinilla, C., Cortese, I., Pascal, J., Tzou, A., McFarland, H.F., Houghten, R.A., Martin, R. Minimal peptide length requirements for CD4 T cell clones-implications for molecular mimicry and T cell survival. Int. Immunol. 12:375-383, 2000.
  56. Hemmer, B., Pinilla, C., Gran, B., Vergelli, M., Ling, N., Conlon, P., McFarland, H.F., Houghten, R.A., Martin, R. Contribution of individual amino acids within MHC molecule or antigenic peptide to TCR ligand potency. J. Immunol. 164:861-871, 2000.
  57. Houghten, R.A., Wilson, D.B., Pinilla, C. Drug and vaccine discovery using mixture-based synthetic combinatorial libraries. Drug Discovery Today 5:276-285, 2000.
  58. Pinilla, C., Appel, J.R., Blondelle, S.E., Dooley, C.T., Eichler, J., Nefzi, A., Ostresh, J.M., Martin, R., Wilson, D.B., Houghten, R.A. Synthesis and screening of positional scanning synthetic combinatorial libraries. In: Combinatorial Chemistry: A Practical Approach (Fenniri, H., Ed.), Oxford University Press, Oxford, pp. 51-74, 2000.
  59. Pinilla, C., Houghten, R.A., Wilson, D.B., Martin, R. Identification and optimization of antigens for T cell clones of clinical relevance using positional scanning combinatorial libraries. In: Peptides for the New Millenium, Proceedings of the 16th American Peptide Symposium (Fields, G.B., Tam, J.P., Barany, G., Eds.), Kluwer Academic Publishers, Dordrecht, The Netherlands, pp. 683-684, 2000.
  60. Hemmer, B., Gran, B., Zhao, Y., Marques, A., Pascal, J., Tzou, A., Kondo, T., Cortese, I., Bielekova, B., Straus, S., McFarland, H.F., Houghten, R.A., Simon, R., Pinilla, C., Martin, R. Identification of candidate T cell epitopes and molecular mimics in chronic Lyme disease. Nature Medicine 5:1375-1382, 1999.
  61. Houghten, R.A., Pinilla, C., Appel, J.R., Blondelle, S.E., Dooley, C.T., Eichler, J., Nefzi, A., Ostresh, J.M. Mixture-based synthetic combinatorial libraries. J. Med. Chem. 42:3743-3778, 1999.
  62. Markovic-Plese, S., Pinilla, C., Martin, R. Molecular mimicry in multiple sclerosis: New insights from studying T cell receptor degeneracy. Immunology News 6:185-186, 1999.
  63. Pinilla, C., Appel, J.R., Houghten, R.A. Positional scanning combinatorial libraries: How and why complex mixtures work. In: Innovation and Perspectives in Solid Phase Synthesis & Combinatorial Chemical Libraries (R. Epton, Ed.), Mayflower Scientific, Ltd., Birmingham, UK, pp.159-162, 1999.
  64. Pinilla, C., Appel, J.R., Buencamino, J., Campbell, G.D., Eichler, J., Greenspan, N.S., Houghten, R.A. Synthetic combinatorial libraries for the study of molecular mimicry: identification of an all D-amino acid peptide recognized by an anti-carbohydrate antibody. In: Peptides Frontiers of Peptide Science/Proc. 15th Am Pep Symp (Tam, J.P. and Kaumaya, P.T.P, Eds.), Kluwer Academic Publishers, Dordrecht, The Netherlands, 761-762, 1999.
  65. Pinilla, C., Martin, R., Gran, B., Appel, J.R., Boggiano, C., Wilson, D.B., Houghten, R.A. Exploring immunological specificity using synthetic peptide combinatorial libraries. Current Opinion in Immunology 11:193-202, 1999.
  66. Wilson, D., Pinilla, C., Wilson, D.H., Schroder, K, Boggiano, C., Judkowski, V., Kaye, J., Hemmer, B., Martin, R., Houghten, R. Immunogenicity. I. Use of peptide libraries to identify epitopes that activate clonotypic CD4+ T cells and induce T cell responses to native peptide ligands. J. Immunol.  163:6424-6434, 1999.
  67. Appel, J.R., Campbell, G.D., Buencamino, J., Houghten, R.A, Pinilla, C. Characterization of antigen-antibody interactions using single substitution analogs and mixture-based synthetic combinatorial libraries. J. Pept. Res. 52:346-355, 1998.
  68. Hemmer, B., Pinilla, C., Appel, J., Pascal, J., Houghten, R., Martin, R. The use of soluble synthetic peptide combinatorial libraries to determine antigen recognition of T cells. J. Pept. Res. 52:338-345, 1998.
  69. Hemmer, B., Vergelli, M., Gran, B., Ling, N., Conlon, P., Pinilla, C., Houghten, R., McFarland, H.F., Martin, R. Cutting edge: Predictable TCR antigen recognition based on peptide scans leads to the identification of agonist ligands with no sequence homology. J. Immunol. 160:3631-3636, 1998.
  70. Hemmer, B., Vergelli, M., Pinilla, C., Houghten, R., Martin, R. Probing degeneracy in T-cell recognition using peptide combinatorial libraries. Immunology Today 19:163-168, 1998.
  71. Pinilla, C., Appel, J.R., Campbell, G.D., Buencamino, J., Benkirane, N., Muller, S., Greenspan, N. All-D peptides recognized by an anti-carbohydrate antibody identified from a positional scanning library. J. Mol. Biol. 283:1013-1025, 1998.
  72. Williamson, R.A., Peretz, D., Pinilla, C., Ball, H.; Bastidas, R.B., Rozenshteyn, R., Houghten, R.A., Prusiner, S.B., Burton, D.R. Mapping the prion protein using recombinant antibodies J.Virol. 72:9413-9418, 1998.
  73. Peretz, D., Williamson, R.A., Matsunaga, Y., Serban, H., Pinilla, C., Bastidas, R.B., Rozenshteyn, R., James, T.L., Houghten, R.A., Cohen, F.E., Prusiner, S.B., Burton, D.R. A conformational transition at the N terminus of the prion protein features in formation of the scrapie isoform. J. Mol. Biol. 273:614-622, 1997.
  74. Pinilla, C., Appel, J.R., Houghten, R.A. The generation of peptide combinatorial libraries using tea-bag synthesis: identification of B-cell epitopes. In: Immunology Methods Manual (Lefkovits, I., Eds.), Academic Press Ltd., San Diego, pp. 836-845, 1997.
  75. Appel, J.R., Buencamino, J., Houghten, R.A., Pinilla, C. Exploring antibody polyspecificity using synthetic combinatorial libraries. Mol. Div. 2:29-34, 1996.
  76. Appel, J.R., Buencamino, J., Houghten, R.A., Pinilla, C. Mapping the specificity of an antibody against an oncogenic sequence using peptide combinatorial libraries and substitution analogs: Implications for breast cancer detection. In: Peptides, Proceedings of the 14th American Peptide Symposium (Kaumaya, P., Eds.), 1996.
  77. Appel, J.R., Muller, S., Benkirane, N., Houghten, R.A., Pinilla, C. Highly specific, cross-reactive sequences recognized by an anti-HBsAg antibody identified from a positional scanning synthetic combinatorial library. Peptide Res. 9:174-182, 1996.
  78. Dörner, B., Blondelle, S.E., Pinilla, C., Appel, J., Dooley, C.T., Eichler, J., Ostresh, J.M., Pérez-Payá, E., Houghten, R.A. Soluble synthetic combinatorial libraries: The use of molecular diversities for drug discovery. In: Combinatorial Libraries. Synthesis, Screening and Application Potential (Cortese, R., Ed.), Walter de Gruyter & Co., New York, pp. 1-25, 1996.
  79. Eichler, J., Lucka, A.W., Pinilla, C., Houghten, R.A. Novel α-glucosidase inhibitors identified using multiple cyclic peptide combinatorial libraries. Mol. Div. 1:233-240, 1996.
  80. Pinilla, C., Appel, J.R., Houghten, R.A. Tea bag synthesis of positional scanning synthetic combinatorial libraries and their use for mapping antigenic determinants. In: Methods In Molecular Biology: Epitope MappIn:g Protocols (Morris, G. E., Eds.), Humana Press In:c., Totowa, NJ, pp. 171-179, 1996.
  81. Pinilla, C., Appel, J.R., Blondelle, S.E., Dooley, C.T., Dörner, B., Eichler, J., Ostresh, J.M., Houghten, R.A. Synthetic combinatorial libraries screened in solution. In: Peptides: Chemistry, Structure and Biology, Proceedings of the Fourteenth American Peptide Symposium (Kaumaya, P.T.P. and Hodges, R.S., Eds.), Mayflower Scientific, Ltd., Kingswinford, UK, pp. 884-886, 1996.
  82. Pinilla, C., Appel, J.R., Dooley, C.T., Blondelle, S.E., Eichler, J., Dörner, B., Ostresh, J.M., Houghten, R.A. The versatility of nonsupport-bound combinatorial libraries. In: Combinatorial Peptide and Nonpeptide Libraries (Jung, G., Ed.), Verlag Chemie, Wienheim, pp. 139-171, 1996.
  83. Appel, J.R., Buencamino, J., Houghten, R.A., Pinilla, C. Study of peptide-antibody interactions using a decapeptide positional scanning library. In: Peptides 94: Proceedings of the 23rd European Peptide Symposium (Maia, H. L. S., Eds.), ESCOM, Leiden, pp. 815-816, 1995.
  84. Blondelle, S.E., Pérez-Payá, E., Dooley, C.T., Pinilla, C., Houghten, R.A. Soluble combinatorial libraries of organic, peptidomimetic and peptide diversities. Trends Anal. Chem. 14:83-92, 1995.
  85. Eichler, J., Appel, J.R., Blondelle, S.E., Dooley, C.T., Dörner, B., Ostresh, J.M., Pérez-Payá, E., Pinilla, C., Houghten, R.A. Peptide, peptidomimetic and organic synthetic combinatorial libraries. Med. Res. Rev. 15:481-496, 1995.
  86. Mingarro, I., Pérez-Payá, E., Pinilla, C., Appel, J.R., Houghten, R.A., Blondelle, S.E. Activation of bee venom phospholipase A2 through a peptide-enzyme complex. FEBS Letters 372:131-134, 1995.
  87. Pinilla, C., Appel, J.R., Houghten, R.A. Synthetic peptide libraries for research and drug discovery. In: Immunological Recognition of Peptides in Medicine and Biology (Zegers, N., Boersma, W., and Claassen, C., Eds.), TNO Prevention and Health, The Netherlands, pp. 1-14, 1995.
  88. Pinilla, C., Appel, J.R., Blondelle, S.E., Dooley, C.T., Dörner, B., Eichler, J., Ostresh, J.M., Houghten, R.A. A review of the utility of peptide combinatorial libraries. Biopolymers (Peptide Science) 37:221-240, 1995.
  89. Pinilla, C., Buencamino, J., Appel, J.R., Hopp, T.P., Houghten, R.A. Mapping the detailed specificity of a calcium-dependent monoclonal antibody through the use of soluble positional scanning combinatorial libraries: Identification of potent calcium-independent antigens. Mol. Div. 1:21-28, 1995.
  90. Pinilla, C., Buencamino, J., Appel, J.R., Houghten, R.A., Brassard, J.A., Ruggeri, Z.M. Two antipeptide monoclonal antibodies that recognize adhesive sequences in fibrinogen: Identification of antigenic determinants and unrelated sequences using synthetic combinatorial libraries. Biomedical Peptides, Proteins & Nucleic Acids 1:199-204, 1995.
  91. Pinilla, C., Buencamino, J., Houghten, R.A., Appel, J.R. Detailed studies of antibody specificity using synthetic peptide combinatorial libraries. In: Vaccines 1995: Molecular Approaches to the Control of Infectious Diseases (Brown, F., Chanock, R. M., Ginsberg, H. S., and Norrby, E., Eds.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp. 1-6, 1995.
  92. Pinilla, C., Buencamino, J., Houghten, R.A., Appel, J.R. Detailed studies of antibody specificity using synthetic peptide combinatorial libraries. In: Peptides 94: Proceedings of the 23rd European Peptide Symposium (Maia, H. L. S., Eds.), ESCOM, Leiden, pp. 113-114, 1995.
  93. Pinilla, C., Chendra, S., Appel, J.R., Houghten, R.A. Elucidation of monoclonal antibody polyspecificity using synthetic combinatorial library. Peptide Res. 8:250-257, 1995.
  94. Churchill, M.E.A., Stura, E., Pinilla, C., Appel, J.R., Houghten, R.A., Kono, D.H., Balderas, R.S., Fieser, G.G., Schulze-Gahmen, U., Wilson, I.A. Crystal structure of a peptide complex of anti-influenza peptide antibody Fab 26/9: Comparison of two different antibodies bound to the same peptide antigen. J. Mol. Biol. 241:534-556, 1994.
  95. Eichler, J., Pinilla, C., Chendra, S., Appel, J.R., Houghten, R.A. Synthesis of peptide libraries on cotton carriers: methods and applications. In: Innovation and Perspectives in Solid Phase Synthesis - Peptides, Proteins and Nucleic Acids (Epton, R., Ed.), Mayflower Worldwide Limited, Birmingham, pp. 227-232, 1994.
  96. Houghten, R.A., Appel, J.R., Blondelle, S.E., Cuervo, J.H., Dooley, C.T., Eichler, J., Pinilla, C. Optimal peptide length determination using synthetic peptide combinatorial libraries. In: Peptides: Proceedings of the 13th American Peptide Symposium (RS Hodges and JA Smith, Eds.) ESCOM, Leiden, pp. 971-974, 1994.
  97. Pinilla, C., Appel, J.R., Houghten, R.A. Identification of antigenic determinants using synthetic peptide combinatorial libraries. In: Current Protocols in Immunology (Coligan, J. E., Kruisbeek, A. M., Margulies, D. H., Shevach, E. M., and Strober, W., Eds.), John Wiley & Sons,Inc, New York, pp. 9.8.1-9.8.15, 1994.
  98. Pinilla, C., Appel, J.R., Houghten, R.A. Investigation of antigen-antibody interactions using a soluble nonsupport-bound synthetic decapeptide library composed of four trillion sequences. Biochem. J. 301:847-853, 1994.
  99. Pinilla, C., Appel, J.R., Blondelle, S.E., Dooley, C.T., Eichler, J., Ostresh, J.M., Houghten, R.A. Versatility of positional scanning synthetic combinatorial libraries for the identification of individual compounds. Drug Dev. Res. 33:133-145, 1994.
  100. Pinilla, C., Appel, J.R., Milich, D., Houghten, R.A. Identification of an antigenic determinant for the surface antigen of hepatitis B virus using peptide libraries. In: Peptides: Chemistry, Structure and Biology, Proceedings of the 13th American Peptide Symposium (Hodges, R. S. and Smith, J. A., Eds.), ESCOM, Leiden, pp. 1016-1017, 1994.
  101. Pinilla, C., Appel, J.R., Houghten, R.A. Functional importance of amino acid residues making up peptide antigenic determinants. Mol. Immunol. 30:577-585, 1993.
  102. Pinilla, C., Appel, J.R., Houghten, R.A. Positional scanning synthetic peptide combinatorial libraries. In: Peptides 1992: Proceedings of the 22nd European Peptide Symposium (Schneider, C. H. and Eberle, A. N., Eds.), ESCOM Science Publishers B.V., Leiden, pp. 65-66, 1993.
  103. Pinilla, C., Appel, J.R., Houghten, R.A. Synthetic peptide combinatorial libraries (SPCLs): Identification of the antigenic determinant of β-endorphin recognized by monoclonal antibody 3E7. Gene 128:71-76, 1993.
  104. Pinilla, C., Appel, J.R., Chendra, S., Houghten, R.A. Determination of multiple binding specificities of a monoclonal antibody using a synthetic peptide combinatorial library. In: Peptides 1992: Proceedings of the 22nd European Peptide Symposium (Schneider, C. H. and Eberle, A. N., Eds.), ESCOM Science Publishers B.V., Leiden, pp. 903-904, 1993.
  105. Appel, J.R., Pinilla, C., Houghten, R.A. Identification of related peptides recognized by a monoclonal antibody using a synthetic peptide combinatorial library. Immunomethods 1:17-23, 1992.
  106. Büttner, K., Pinilla, C., Appel, J.R., Houghten, R.A. Anomalous reversed-phase high-performance liquid chromatographic behaviour of synthetic peptides related to antigenic helper T cells sites. J. Chromatography 625:191-198, 1992.
  107. Houghten, R.A., Appel, J.R., Blondelle, S.E., Cuervo, J.H., Dooley, C.T., Pinilla, C. The use of synthetic peptide combinatorial libraries for the identification of bioactive peptides. Biotechniques 13:412-421, 1992.
  108. Houghten, R.A., Appel, J.R., Blondelle, S.E., Cuervo, J.H., Dooley, C.T., Pinilla, C. The use of synthetic peptide combinatorial libraries for the identification of bioactive peptides. Pept. Res. 5:351-358, 1992.
  109. Houghten, R.A., Cuervo, J.H., Pinilla, C., Appel, J.R., Dooley, C.T., Blondelle, S.E. The use of a peptide library composed of 34 012 224 hexamers for basic research and drug discovery. In: Peptides, Proceedings of the Twelfth American Peptide Symposium (JA Smith and JE Rivier, Eds.) ESCOM Science Publishers B.V. Leiden, pp. 560-561, 1992.
  110. Pinilla, C., Appel, J., Houghten, R.A. Synthetic peptide combinatorial libraries: The screening of tens of millions of peptides for basic research and drug discovery. In: Vaccines 92 (Brown, F., Chanock, R. M., Ginsberg, H., and Lerner, R. A., Eds.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp. 25-28, 1992.
  111. Pinilla, C., Appel, J.R., Blanc, P., Houghten, R.A. Rapid identification of high affinity peptide ligands using positional scanning synthetic peptide combinatorial libraries. Biotechniques 13:901-905, 1992.
  112. Pinilla, C., Appel, J.R., McPherson, S.E., Houghten, R.A. Comparison of structural and functional approaches for the study of peptide-mAb interactions. In: Peptides. Proceedings of the Twelfth American Peptide Symposium (Smith, J. A. and Rivier, J. E., Eds.), ESCOM Science Publishers B.V., Leiden, pp. 867-868, 1992.
  113. Houghten, R.A., Pinilla, C., Blondelle, S.E., Appel, J.R., Dooley, C.T., Cuervo, J.H. Generation and use of synthetic combinatorial libraries for basic research and drug discovery. Nature 354:84-86, 1991.
  114. Pinilla, C., Appel, J.R., Houghten, R.A. Peptide-monoclonal antibody interactions defined at the amino acid level: Advantages of competitive ELISA techniques. In: Peptides 1990: Proceedings of the 21st European Peptide Symposium (Giralt, E. and Andreu, D., Eds.), ESCOM Science Publishers B.V., Leiden, pp. 860-861, 1991.
  115. Appel, J.R., Pinilla, C., Niman, H., Houghten, R.A. Elucidation of discontinuous linear determinants in peptides. J. Immunol. 144:976-983, 1990.
  116. Houghten, R.A., Appel, J.R., Pinilla, C. The effects of induced conformational changes on the antigenicity and immunogenicity of synthetic branched peptides polymers. In: Peptides 1988 - Proceedings of the 20th European Peptide Symposium (Jung, G. and Bayer, E., Eds.), Walter de Gruyter & Co., Berlin, pp. 217-21, 1989.
  117. Houghten, R.A., Appel, J., Pinilla, C. The use of large numbers of synthetic peptide analogs as probes for the detailed study of antibody/antigen interactions. In: Peptide Chemistry 1987 (Shiba, T. and Sakakibara, S., Eds.), Protein Research Foundation, Osaka, pp. 769-774, 1988.
  118. Houghten, R.A., Appel, J.R., Pinilla, C. Use of multiple peptide analogs as probes in the detailed study of antibody-antigen interactions. In: Vaccines 88 (Ginsberg, H., Brown, F., Lerner, R. A., and Chanock, R. M., Eds.), Cold Spring Harbor, New York, pp. 9-12, 1988.
  119. Patarroyo, M.E., Romero, P., Torres, M.L., Clavijo, P., Andreu, D., Lozada, D., Sanchez, L., Del Portillo, P., Pinilla, C., Moreno, A., Alegria, A., Houghten, R.A. Protective synthetic peptides against experimental Plasmodium falciparium-induced malaria. In: Vaccines 87 (Chanock, R. M., Ginsberg, H., Lerner, R. A., and Brown, F., Eds.), Cold Spring Harbor Laboratory, New York, pp. 117-124, 1987.

Patents

  1. Dialkyl ureas as calcitonin mimetics. U.S. Patent No. 6,391,917. Issued May 21, 2002.  Inventors:  Petrie, C.R., McKernan, P.A., Moore, E.E., Ostresh, J.M., Meyer, J.-P., Houghten, R.A., Pinilla, C.
  2. Dimeric oligopeptide mixture sets. U.S. Patent No. 6,287,787. Issued September 11, 2001.  Inventors:  Houghten, R.A., Pinilla, C.
  3. Dialkyl ureas as calcitonin mimetics. U.S. Patent No. 6,255,351. Issued July 3, 2001.  Inventors:  Petrie, C.R., McKernan, P.A., Moore, E.E., Ostresh, J.M., Meyer, J.-P., Houghten, R.A., Pinilla, C.
  4. Dialkyl ureas as calcitonin mimetics. U.S. Patent No. 6,221,913. Issued April 24, 2001.  Inventors:  Petrie, C.R., McKernan, P.A., Moore, E.E., Ostresh, J.M., Meyer, J.-P., Houghten, R.A., Pinilla, C.
  5. Peptides having anti-melittin activity. U.S. Patent No. 5,698,673. Issued December 16, 1997.  Inventors:  Blondelle, S.E., Pinilla, C., Houghten, R.A.
  6. Scanning synthetic peptide combinatorial libraries: Oligopeptide mixture sets having one predetermined residue at a single, predetermined position, methods of making and using the same. U.S. Patent No. 5,556,762. Issued September 17, 1996.  Inventors:  Pinilla, C., Appel, J.R., Houghten, R.A.
  7. Equimolar multiple oligomer mixtures, especially oligopeptide mixtures. U.S. Patent No. 5,504,190. Issued April 2, 1996.  Inventors:  Houghten, R.A., Cuervo, J.H., Pinilla, C., Appel, J.R., Blondelle, S.E.
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