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
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 suprpression of 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. 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 peptidominetics from CD2 protin to disrupt the interaction CD2 and LFA3 proteim molecules.
2. Design of small molecular inhibitors targeted towards HER-2 as therapeutic agents for breast 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 over expression 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 (erB-2 or neu) are the growth factors that have implications in cancer. The over expression or activation of HER-2 occurs fequently in breast, ovarian and lung cancers. HER-2 oncogene in human breast carcinomas has been associated with a more aggressive course of the disease. Thus, HER-2 has become an important therapeutic target in breast cancer. Antibodies and small molecules are being targeted against HER-2 and has resulted in an antibody drug trastzumab (Herceptin®, Genentech, Inc., CA). Recently, the crystal structure of HER-2 with antibody herceptin has been reported. The small molecules developed against HER-2 previously were based on the homology modeling of HER-2 since the crystal structure was not available. In this project we propose to design HER-2 targeted molecules based on the complex of crystal structure of the complex of HER-2-herceptin. The herceptin binding site encompasses a pocket-like structure which may accommodate binding of small molecules, peptides or peptidomimetics. Peptides/peptidomimetics will be designed which may interrupt HER-2 and ErbB receptor interactions and hence may act as therapeutic agents for HER-2 over expressing breast cancer.
|Seetharama D. S. Jois, Ph.D.
Associate Professor of Medicinal Chemistry
Department of Basic Pharmaceutical Sciences
School of Pharmacy
1800 Bienville Dr
University of Louisiana at Monroe
Monroe, LA 71201