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Sudhir Paul, Ph.D. Professor and Director Fax: (713) 500-0574 |
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Research Interests: Development of covalent binding and
catalytic activity in antibodies (Abs); functional role of catalytic Abs to
HIV, HCV, amyloid peptide and neuropeptides; vaccines that induce protective catalytic
antibodies; antigen-specific B cell tolerance induction in hemophilia.
We discovered that Abs can catalyze the cleavage of polypeptides. We are studying the structural factors that permit coordinated noncovalent binding and chemical activity of the Abs using biophysical and biochemical techniques. From the basic science studies, we are learning new ways to induce the synthesis of proteolytic Abs for protection against microbial proteins and toxic endogeous proteins. Electrophilic analogs of the antigens are used to enhance the innate nucleophilic reactivity of the Abs. This can result in Abs that bond to polypeptides covalently via nucleophile-electrophile pairing. If a water molecule is properly positioned in the active site, the enhanced nucleophilicity leads to hydrolysis of peptide bonds. Proteolytic Abs inactivate the antigen permanently and a single molecule of the Ab can be reused to cleave thousands of antigen molecules. Induction of these Abs holds the hope of a new generation of vaccines and passive immunotherapeutic applications. Our translational studies are in the areas of HIV infection, HCV infection and removal of amyloid plaques in Alzheimer’s disease. The reverse problem is accumulation of pathogenic antibodies directed to self-proteins in autoimmune disease. Based on our discovery that all antibodies contain a nucleophile in their combining sites, we have developed analogs of polypeptides that can bind covalently to the B cell receptors (BCRs), consisting of Abs complexed to signal transduction proteins. Other researchers have shown that saturation of the BCRs results in B cell apoptosis and tolerance. We are testing the idea that covalent antigen analogs can induce tolerance in an antigen-specific manner by permanent engagement of the BCRs. Hemophilia A, in which Abs to Factor VIII are the cause of the bleeding disorder is under study as the initial model in which we hope to induce tolerance to Factor VIII.
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Selected Publications Taguchi, H., Planque, S., Nishiyama, Y., Symersky, J., Boivin, S., Szabo, P., Friedland, R.P., Ramsland, P.A., Edmundson, A.B., Weksler, M.E., Paul, S. Autoantibody catalyzed hydrolysis of amyloid β peptide. J. Biol. Chem. 283:4714-4722, 2008. Pubmed. Planque, S., Mitsuda, Y., Taguchi, H., Salas, M., Morris, M.-K., Nishiyama, Y., Kyle, R., Okhuysen, P., Escobar, M., Hunter, R., Sheppard, H.W., Hanson, C., Paul, S. Characterization of gp120 hydrolysis by IgA antibodies from humans without HIV infection. AIDS Research and Human Retroviruses. 23:1541-1553, 2007. Pubmed. Nishiyama, Y., Mitsuda, Y., Taguchi, H., Planque, S., Salas, M., Hanson, C.V., and Paul, S. Towards covalent vaccination: Improved polyclonal HIV neutralizing antibody response induced by an electrophilic gp120 V3 peptide analog. J. Biol. Chem. 282:31250-31256, 2007. Pubmed. Mitsuda, Y., Planque, S., Hara, M., Kyle, R., Taguchi, H., Nishiyama, Y., and Paul, S. Naturally occurring catalytic antibodies: Evidence for preferred development of the catalytic function in IgA class antibodies. Mol. Biotechnol. 36:113-122, 2007. Pubmed. Nishiyama, Y., Karle, S., Planque, S., Taguchi, H., Paul, S. Antibodies to the superantigenic Site of HIV-1 gp120: Hydrolytic and binding activities of the light chain subunit. Mol. Immunol. 44:2707-2718, 2007. Pubmed. Nishiyama, Y., Karle, S., Mitsuda, Y., Taguchi, H., Planque, S., Salas, M., Hanson, C., and Paul, S. Towards irreversible HIV inactivation: stable gp120 binding by nucleophilic antibodies. J. Mol. Recognit. 19:423-431, 2006. Pubmed. Paul, S., and Planque, S. (2006) Antibody engineering. In: Nature Encyclopedia of Life Sciences, London: Nature Publishing Group, John Wiley & Sons, Ltd: Chichester http://www.els.net/ [DOI: 10.1038/npg.els.0001278], Published online: January 27, 2006. Paul, S., Nishiyama, Y., Planque, S., and Taguchi, H. Theory of proteolytic antibody occurrence. Immunol. Lett. 103:8-16, 2006. Pubmed Hanson, C.V., Nishiyama, Y., and Paul, S. Catalytic antibodies and their applications. Curr Opin Biotechnol. 16:631-636, 2005. Pubmed. Nishiyama, Y., Mitsuda, Y., Taguchi, H., Planque, S., Hara, M., Karle, S., Hanson, C.V., Taizo, U., and Paul, S. Broadly distributed reactivity of proteins coordinated with specific ligand binding activity. J. Mol. Recognit. 18:295-306, 2005. Pubmed Paul, S., Nishiyama, Y., Planque, S., Karle, S., Taguchi, H., Hanson, C., and Weksler. M.E. Antibodies as Defensive Enzymes. Springer Semin. Immun. 26:485–503, 2005. Pubmed Paul, S., Karle, S., Planque, S., Taguchi, H., Salas, M., Nishiyama, Y., Handy, B., Hunter, R., Edmundson, A., and Hanson, C. Naturally occurring proteolytic antibodies: Selective IgM-catalyzed hydrolysis of HIV gp120. J. Biol. Chem. 279:39611-39619, 2004. Pubmed Taguchi, H., Keck, Z., Foung, S.K.H., Paul, S. and Nishiyama, Y. Antibody light chain-catalyzed hydrolysis of a hepatitis C virus peptide. Bioorg. Med. Chem. Lett. 14:4529-4532, 2004. Pubmed Voice, J., Donnelly, S., Dorsam, G., Dolganov, G., Paul, S. and Goetzl, E.J. c-Maf and JunB mediation of Th2 differentiation induced by the type 2 G protein-coupled receptor (VPAC2) for vasoactive intestinal peptide. J. Immunol. 172:7289-7296, 2004. Pubmed Keck, Z., Sung, V.M.H., Perkins, S., Rowe, J., Paul, S., Liang, T.J., Lai, M.M.C. and Foung, S.K.H. Human monoclonal antibody to hepatitis C virus E1 glycoprotein that blocks virus attachment and viral infectivity. J. Virol. 78: 7257–7263, 2004. Pubmed Le, A., Dasgupta, S., Planque, S., Paul, S. and Thiagarajan, P. Lupus-derived antiprothrombin autoantibodies from a V gene phage display library are specific for the kringle 2 domain of prothrombin. Biochemistry. 43:4047-4054, 2004. Pubmed Planque, S., Bangale, Y., Karle, S., Taguchi, H., Poindexter, B., Bick, R., Edmundson, A., Nishiyama, Y. and Paul, S. Ontogeny of proteolytic immunity: IgM serine proteases. J. Biol. Chem.279:14024-14032, 2004. Pubmed Nishiyama, Y., Bhatia, G., Bangale, Y., Planque, S., Mitsuda, Y., Taguchi, H., Karle, S., and Paul, S. Towards selective covalent inactivation of pathogenic antibodies: A phosphonate diester analog of vasoactive intestinal peptide that Inactivates catalytic autoantibodies. J. Biol. Chem. 279:7877–7883, 2004. Pubmed Karle, S., Planque, S., Nishiyama, Y., Taguchi, H., Zhou, Y.-X., Salas, M., Lake, D., Thiagarajan, P., Arnett, F., Hanson, C.V., and Paul, S. Cross-clade HIV-1 neutralization by an antibody fragment from a lupus phage display library. AIDS. 18:329–347, 2004. Rangan, S.K., Liu, R., Brune, D., Planque, S., Paul, S., and Sierks, M.R. Degradation of β-amyloid by Proteolytic Antibody Light Chains. Biochemistry. 42:14328-14334, 2003. Pubmed Paul, S., Planque, S., Zhou, Y.-X., Taguchi, H., Bhatia, G., Karle, S., Hanson, C., and Nishiyama, Y. Specific HIV gp120 cleaving antibodies induced by covalently reactive analog of gp120. J. Biol. Chem. 278:20429-20435, 2003. PubMed Planque, S., Taguchi, H., Burr, G., Bhatia, G., Karle, S., Zhou, Y.-X., Nishiyama, Y., and Paul, S. Broadly distributed chemical reactivity of natural antibodies expressed in coordination with specific antigen bonding activity. J. Biol. Chem. 278:20436 - 20443, 2003. PubMed Bangale, Y., Karle, S., Zhou, Y.-X., Li, L., Kalaga, R., and Paul, S. VIPase autoantibodies in Fas-defective mice and patients with autoimmune disease. FASEB J. 17:628-635, 2003. PubMed Karle, S., Nishiyama, Y., Zhou, Y.-X., Luo, J., Planque, S., Hanson, C., and Paul, S. Carrier-dependent specificity of antibodies to a conserved peptide determinant of gp120. Vaccine. 21:1213–1218, 2003. PubMed Planque, S., Zhou, Y.-X., Nishiyama, Y., Sinha, M., O'Connor-McCourt, M., Arnett, F. C., and Paul, S. Autoantibodies to the epidermal growth factor receptor in systemic sclerosis, lupus and autoimmune mice. FASEB J. 17:136-143 2003. PubMed Voice, J. K., Grinninger, C., Kong, Y., Bangale, Y., Paul, S., and Goetzl, E. J. Roles of vasoactive intestinal peptide (VIP) in the expression of different immune phenotypes by wild-type mice and T cell-targeted type II VIP receptor transgenic mice. J. Immunol. 170:308-314, 2003. PubMed Bangale, Y., Cavill, D., Gordon, T., Planque, S., Taguchi, H., Bhatia, G., Nishiyama, Y., Arnett, F., and Paul, S. Vasoactive intestinal peptide binding autoantibodies in autoimmune humans and mice. Peptides. 23:2251-2257, 2002. PubMed Taguchi, H., Burr, G., Karle, S., Planque, S., Zhou, Y.-X., Paul, S., and Nishiyama, Y. A mechanism-based probe for gp120-hydrolyzing antibodies. Bioorg. Med. Chem. Lett. 12:3167–3170, 2002. PubMed Zhou, Y.-X., Karle, S., Taguchi, H., Planque, S., Nishiyama, Y., and Paul, S. Prospects for immunotherapeutic proteolytic antibodies. J. Immunol. Methods. 269:257-268, 2002. PubMed Nishiyama, Y., Taguchi, H., Luo, J., Zhou, Y.-Z., Burr, G., Karle, S., and Paul, S. Covalent reactivity of a phosphonate monophenyl ester with serine proteinases: An overlooked feature of oxyanionic transition state analogs. Arch. Biochim. Biophys. 402:281–288, 2002. PubMed Aleksandrova, E. S., Koralevski, F., Titov, M. I., Demin, A.V., Kozyr', A. V., Kolesnikov, A. V., Tramontano, A., Paul, S., Thomas, D., Gabibov, A. G., Gnuchev, N. V., and Friboulet, A. A structure-activity study of a catalytic antiidiotypic antibody to the human erythrocyte acetylcholinesterase. Bioorg Khim. 28:118-125, 2002. PubMed Berisha, H. I., Bratut, M., Bangale, Y., Colasurdo, G., Paul, S., and Said, S. I. New evidence for transmitter role of VIP in the airways: Impaired airway relaxation by a catalytic antibody to VIP. Pulm. Pharmacol. Ther. 15:121-127, 2002. PubMed Alexandrova, E. S., Koralewski, F., Titov, M. I., Demin, A. V., Ignatova, A. N., Kozyr, A. V., Kolesnikov, A. V., Tramontano, A., Paul, S., Thomas, D., Gabibov, A. G., and Friboulet, A. Catalysis of esterolytic reactions by the anti-idiotypic antibody against human erythrocyte acetylcholinesterase. Dokl. Biochem. Biophys. 377:75-78, 2001. PubMed Paul, S., Tramontano, A., Gololobov, G., Zhou, Y.-X., Taguchi, H., Karle, S., Nishiyama, Y., Planque, S., and George, S. Phosphonate ester probes for proteolytic antibodies. J. Biol. Chem. 276:28314-28320, 2001. PubMed Kolesnikov, A. V., Kozyr, A. V., Alexandrova, E. S., Koralewski, F., Demin, A. V., Titov, M. I., Avalle, B., Tramontano, A., Paul, S., Thomas, D., Gabibov, A. G., and Friboulet, A. Enzyme mimicry by the anti-idiotypic antibody approach. Proc. Natl. Acad. Sci. 97:13526-13531, 2000. PubMed Thiagarajan, P., Dannenbring, R., Matsuura, K., Tramontano, A., Gololobov, G., and Paul, S. A monoclonal antibody light chain with prothrombinase activity. Biochemistry. 39:6459-6465, 2000. PubMed Thiagarajan, P. and Paul, S. Prothrombin cleaving antibody light chains. In: Chemical Immunology: Catalytic Antibodies. (S. Karger AG, Basel, Switzerland) Ed., S. Paul. Vol. 77, pp. 115-129, 2000. Karger Tramontano, A., Gololobov, G., and Paul, S. Proteolytic antibodies: Origins, selection and induction. In: Chemical Immunology: Catalytic Antibodies. (S. Karger AG, Basel, Switzerland) Ed., S. Paul. Vol. 77, pp. 1-17, 2000. Karger Paul, S., Ed. Chemical Immunology: Catalytic Antibodies. (S. Karger AG, Basel, Switzerland) Vol. 77, pp. 1-158, 2000. Karger Paul, S., Tramontano, A., Sarma, U., Thomas, D., and Gabibov, A., (Eds.) Proceedings of the 3rd International Conference on Catalytic and Super Antibodies. Appl. Biochem. Biotechnol. 83:1-318, 2000. Li, L., Kalaga, R., and Paul, S. Proteolytic components of serum IgG preparations. Clin. Exp. Immunol. 120:261-266, 2000. PubMed Gololobov, G., Tramontano, A., and Paul, S. Nucleophilic proteolytic antibodies. Appl. Biochem. Biotech. 83:221-232, 2000. PubMed Tramontano, A., Ivanov, B., Gololobov, G., and Paul, S. Inhibition and labeling of enzymes and abzymes by phosphonate esters. Appl. Biochem. Biotech. 83:233-243, 2000. PubMed Paul, S., Kalaga, R., Gololobov, G., and Brenneman, D. Natural catalytic immunity is not restricted to autoantigenic substrates: Identification of a human immunodeficiency virus gp120 cleaving antibody light chain. Appl. Biochem. Biotech. 83:71-84, 2000. PubMed Paul, S. and Tramontano, A. Antibody Catalysis - A Super Activity. The Immunologist. 7:163-168, 1999. Gololobov, G., Sun, M., and Paul, S. Innate antibody catalysis. Mol. Immunol. 36:1215-1222, 1999. PubMed Paul, S., Ed. Autoimmune Reactions (Humana Press, Totowa, NJ) pp 1 - 438,1998. Bosilevac, J. M., Gilchrist, C.A., Jankowski, P.E., Paul, S., Rees, A. R., and Hinrichs, S. H. Inhibition of ATF1 and CREB activated transcription by an intracellular single chain Fv fragment. J. Biol. Chem. 273:16874-16879, 1998. PubMed Ikezaki, H., Paul, S., Alkan-Onyuksel, H., Patel, M., Gao, X.-P., and Rubinstein, I. Vasodilation elicited by liposomal VIP is unimpeded by anti-VIP antibody in hamster cheek pouch. Am. J. Physiol. 275:R56-R62, 1998. PubMed Paul, S. Autoantibody catalysis: No longer hostage to Occam's Razor. Ann. New York Acad. Sci. 865:246-254, 1998. PubMed Gololobov, G., Noda, Y., Sherman, S., Rubinstein, I., Baranowska-Kortylewicz, J., and Paul, S. Stabilization of vasoactive intestinal peptide by lipids. J. Pharmacol. Exp. Ther. 285:753 - 758, 1998. PubMed Kohler, H. and Paul, S. Superantibodies: New players in innate and adaptive immunity. Immunol. Today. 19: 221 - 227, 1998. PubMed Paul, S. VIPASE. In: Handbook of proteolytic enzymes, Barrett A, Woessner F, Rawlings N., Eds. (Academic Press, London, England) pp. 533 - 535, 1998. Paul, S., Friboulet, A., Gabibov, S., and Thomas, D., Eds. Whither Catalytic Antibodies? Proceeding of 2nd International symposium on Catalytic Antibodies and Antibody Engineering. Appl. Biochem. Biotechnol. 75: 1 - 150, 1998. Paul, S. Protein engineering. In: Molecular Biotechniques. Walker J, Ed. (Humana Press, Totowa, NJ), Chapter 43, pp 547 - 566, 1998. Paul, S. Relevance of catalytic anti-VIP antibodies to the airway. In: Pro-inflammatory and anti-inflammatory peptides, Lung Biology in Health and Disease Series, Sami Said, Ed. (Marcel Dekker, New York). Chapter 19, pp 459-475, 1997. Sun, M., Gao, Q.-S., Kirnarskiy, L., Rees, A., and Paul, S. Cleavage specificity of a proteolytic antibody light chain and effects of the heavy chain variable domain. J. Mol. Biol. 271:374-385, 1997. PubMed Kohler, H., Paul, S., and Marchalonis, J. Multifunctional variable domains. The Immunologist. 5:98-103, 1997. Paul, S., Li, L., Kalaga, R., O'Dell, R.E., Dannenbring, Jr, R.E., Swindells, S., Hinrichs, S., Caturegli, P., and Rose, N. Characterization of thyroglobulin-directed and polyreactive catalytic antibodies in autoimmune disease. J. Immunol. 159:1530-1536, 1997. PubMed Sun, M. and Paul, S. Altered cleavage site preference of a proteolytic antibody light chain induced by denaturation. FEBS Lett. 407:289-290, 1997. PubMed Tyutyulkova, S., Gao, Q.-S., Thompson, A., Rennard, S., and Paul, S. Efficient vasoactive intestinal polypeptide hydrolyzing autoantibody light chains selected by phage display. Biochimica. Biophysica. Acta. 1316:217-223, 1996. PubMed Paul, S. Natural catalytic antibodies. Mol. Biotechnol. 5:197-207, 1996. PubMed Paul, S. Proteolytic antibodies. Isr. J. Chem. 36:207-214, 1996. Li, L., Sun, M., Gao, Q.-S., and Paul, S. Low level formation of potent catalytic IgG fragments mediated by disulfide bond instability. Mol. Immunol. 33:593-600, 1996. PubMed Suzuki, H., Noda, Y., Gao, X., Séjourné, F., Alkan-Önyuksel, H., Paul, S., and Rubinstein, I. Encapsulation of VIP into liposomes restores vasorelaxant in hypertension in situ. Am. J. Physiol. (Heart Circ Physiol 40) 271:H282-H287, 1996. Li, L., Paul, S., Tyutyulkova, S., Kazatchkine, M., and Kaveri, S. Catalytic activity of anti-thyroglobulin antibodies. J. Immunol. 154:3328-3332, 1995. PubMed Paul, S., Li, L., Kalaga, R., Wilkins-Stevens, P., Stevens, F. J., and Solomon, A. Natural catalytic antibodies: Peptide hydrolyzing activities of Bence Jones proteins and VL fragment. J. Biol. Chem. 270:15257-15261, 1995. PubMed Tyutyulkova, S., Gao, Q.-S., and Paul, S. Selection of human immunoglobulin light chains from a phage display library. Antibody Engineering Protocols. Ed., Paul S. (Methods in Molecular Biology Series, Humana Press, Totowa, NJ) 51:377-394, 1995. Gao, Q.-S. and Paul, S. Molecular cloning of anti-ground state proteolytic antibody fragments. Antibody Engineering Protocols. Ed., Paul S. (Methods in Molecular Biology Series, Humana Press, Totowa, NJ). 51:281-296, 1995. Paul, S., ed. Antibody Engineering Protocols. (Methods in Molecular Biology Series, Humana Press, Totowa, NJ).51:1-450, 1995. Suzuki, H., Noda, Y., Paul, S., Gao, X.-P., and Rubinstein, I. Encapsulation of vasoactive intestinal peptide into liposomes: Effects on vasodilation in vivo. Life Sciences. 57:1451-1457, 1995. PubMed Kalaga, R., Li, L., O'Dell, J., and Paul, S. Unexpected presence of polyreactive catalytic antibodies in IgG from unimmunized donors and decreased levels in rheumatoid arthritis. J. Immunol. 155:2695-2702, 1995. PubMed Gao, Q.-S., Sun, M., Rees, A., and Paul, S. Site-directed mutagenesis of proteolytic antibody light chain. J. Mol. Biol. 253:658-664, 1995. PubMed |
Updated: February 29, 2008