Graduation Year


Document Type




Degree Granting Department


Major Professor

Mark L. Mclaughlin, Ph.D.

Committee Member

Jianfeng Cai, Ph.D.

Committee Member

Wayne C. Guida, Ph.D.

Committee Member

Rongshi Li, Ph.D.

Committee Member

Roman Manetsch, Ph.D.


protein-protein interaction, mimetics, -helical, non-peptidic


Protein-protein interactions are key to several biological processes that facilitate signal transduction and many other processes. These interactions are involved in pathways that are critical to many human diseases. Targeting specific protein-protein interactions is a challenging goal because protein-protein interactions are predominately through hydrophobic interactions. Antagonists of the protein-protein interactions need to be perfectly fit into the binding pockets to ensure the activity. The -helical domain of the proteins behaves as the recognition motifs for numerous protein-protein, and protein-nucleic acid interactions. Research has shown that pathways of many diseases contain protein-protein interactions involving -helical domains, e.g. neurological disorders, bacterial infections, HIV and cancer, etc. It is difficult yet very important to design small molecules to target the shallow binding areas of protein-protein interactions. So far the most successful one is Hamilton’s 1,4-terphenylene scaffold, which has been used to target the interactions between p53/MDM2, Bak/Bcl-xL etc. Inspired by this, we designed and synthesized three new scaffolds of non-pepditic -helical mimetics, mimicking the i, i + 4, i + 7 positions of an -helix. There are three basic principles that were leading our design. The side chains of our designed molecules should act as mimetics of the side chains of an -helix. Second, our molecules should possess improved water solubility. Third, the molecules should be easy to synthesize to generate a focused library. Some of our molecules, including the ones whose molecular weight are as low as 294, started to show some inhibition against p53/MDM2 interactions.