Protein-protein interactions play an important role in a wide range of physiological and pathological processes. The interaction between the proteins involves small surface binding epitopes. Thus, protein-protein interactions can be modulated by blocking surface epitopes of proteins. Hence, inhibition of protein-protein interaction has a tremendous impact on understanding the structural basis of these interactions and in developing new therapeutic strategies for many human diseases. Our group is focusing on two important areas of research to tweak the protein-protein interactions.
1. Design and structural studies of peptides for cell-adhesion inhibition
The main research interest is in the area of modulation of protein-protein interactions involved in cell-cell adhesion by peptides and peptidomimetics. Modulation of cell adhesion is essential for suppression of the immune response in autoimmune diseases, improving drug delivery through the biological barriers (i.e., intestinal mucosa and blood-brain barriers) and inhibition of tumor metastasis. The design of inhibitors of these interactions and their structural studies is the main goal of the research program. The current research focus is on the design of peptides and peptidomimetics from CD2 protein to disrupt the interaction of CD2 and CD58 (also called LFA3) protein molecules. For the past 12 years, I have designed peptides and peptidomimetics in this particular area. Preliminary in vivo studies using an animal model, collagen-induced arthritis in mice (CIA), indicated that a peptide from CD2 was able to suppress rheumatoid arthritis in mice. Furthermore, with the help of a collaborator, we have shown that these peptides are also effective in modulating the immune response in T cells that are derived from transgenic mice that develop arthritis similar to human arthritis. At present I am working on grafting these peptides to cyclotides, which are plant-derived peptides that have a multicyclic structure with disulfide bonds, are resistant to thermal, chemical, and enzymatic degradation, and are orally bioavailable.
2. Design of small molecular inhibitors targeted towards HER-2 as therapeutic agents for breast and lung cancer.
Growth factors are important mediators of cell proliferation. The interaction of growth factors with their receptors generates signal transduction. The intracellular domains of these receptor proteins are protein tyrosine kinases. The overexpression or activation of these receptors results in uncontrolled cell proliferation. Epidermal growth factor receptor (EGFR) kinase and the related Human Epidermal Growth Factor Receptor-2 (HER-2) are the growth factors that have implications in cancer. The overexpression or activation of HER-2 frequently occurs in breast, ovarian and lung cancers. HER-2 oncogene in human breast carcinomas has been associated with a more aggressive course of the disease. The protein HER2 is known to interact with other EGFRs and form dimers/heteromers. The blockade of protein-protein interactions of HER2 with other EGFRs ultimately leads to control of cell growth and, hence, has therapeutic value for lung cancer patients. Using the three-dimensional structure of HER2 protein and its interaction with other receptors, I have designed novel peptidomimetics that target the extracellular domain of human epidermal growth factor receptor -2 (HER2) and inhibit the dimerization of HER2 with other receptors such as HER2: HER3 and EGFR: HER2. This approach is novel because the peptidomimetic molecule designed disrupts not only EGFR-HER2 dimerization but also HER2-HER3 dimerization. This project is funded by National Cancer Institute (NCI), National Institute of Health (NIH) grant number 1R15CA188225-01A1.
|Seetharama D. S. Jois, Ph.D.
Professor of Medicinal Chemistry
Department of Basic Pharmaceutical Sciences
School of Pharmacy
1800 Bienville Dr
University of Louisiana at Monroe
Monroe, LA 71201