- Paul, S., Planque, S.A., Nishiyama, Y., and Hanson, C.V. A covalent HIV vaccine: Is there hope for the future? Future Virology (Editorial) 4:7-10, 2009. Article.
- 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
Sudhir Paul, PhD
Professor
Director Chemical Immunology Research Center
Pathology & Laboratory Medicine
(713) 500 - 5347
Sudhir.Paul@uth.tmc.edu
Development of Covalent Binding and Catalytic Activity in Antibodies
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; protein chemical reactivity.
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. It turns out that the nucleophilic reactivity is also found in non-antibody receptors. We are exploring the translational implications of this finding in studies involving the use of electrophilic ligand analogs for more sensitive imaging of cancer-associated antigens.
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