The long-term objective of the proposed studies is to understand the chemistry of a new class of ring-shaped (macrocyclic) molecules and the potential that these molecules might have in modulating interactions between proteins. Controlling protein-protein interactions is a largely unexplored area of research and is fertile ground for the discovery of new drug leads and strategies. Academic labs, biotech companies, and big pharma are investing increasing energies into the pursuit of strategies and macrocycles that might accomplish these ends. Preparing rings represents a difficult synthetic challenge that rarely has a general solution. That is, while many methods have been used successfully, they can be limited in scope or substrate specificity. Self-assembly is a powerful alternative to traditional covalent synthesis, but commonly, the results of such strategies are a mixture of products. Fortuitously, simple chemistries proposed here can be affected to make molecules in 4 or 5 steps that spontaneously dimerize to yield a single isolable product. The backbone of these molecules offers numerous sites for manipulation. That is, it can incorporate various groups (or ring size can be varied) to affect both the selectivity and affinity of the macrocycle toward a protein target. Accordingly, the proposed efforts focus on two general aims.
The first aim i s chemical. The generality of the motif will be probed by looking at the substitution tolerances at four different positions within the macrocycle including the choice of amino acid building block incorporated and size of the ring. Subsequently, the products will be assessed for solubility, a factor that can affect the distribution of the molecule across cell membranes and the method used for delivery to organisms. These efforts will be executed in the lab of the PI using primarily undergraduates.
The second aim i s biological. Two collaborating PIs work on Alzheimer's disease and breast cancer. Macrocycles will be prepared using guidance from bioinformatics and computation with the goal of disrupting specific protein-protein interactions that are implicated in the progression of these diseases. Undergraduates will carry out these studies with collaborating PI supervision using circular dichroism and nuclear magnetic resonance spectroscopies.
This proposal investigates a largely unexplored strategy for treating disease by developing a potential new class of drugs. These small, ring shaped molecules are designed to disrupt the interactions between biomolecules called proteins. While manipulating specific protein-protein interactions with specific macrocycles could lead to treatments for many different diseases, this proposal focuses on disrupting protein-protein interactions in Alzheimer?s and breast cancer.