Specific cyclic peptide inhibitors of peptidylprolyl isomerases through fragment-based methods

Speaker Name: 
Chad Townsend
Speaker Organization: 
Biomolecular Engineering and Bioinformatics
Start Time: 
Thursday, July 16, 2015 - 10:00am
End Time: 
Thursday, July 16, 2015 - 11:30am
Location: 
305 Physical Sciences Building
Organizer: 
Scott Lokey

Abstract: Peptidylprolyl isomerases (PPIs) are a family of proteins present in all eukaryotic and prokaryotic cells which regulate cellular functions by catalyzing the transition of proline residue amide bonds from cis to trans in their target proteins. PPIA (Cyclophilin A), the first human PPI identified, has been shown to play roles in protein folding, protein trafficking, immune response, viral infection, and cell signaling. The roles of PPIA have been explored through direct observation techniques and co-crystallization with targets, but not through small molecule or phenotypic methods. This is because there are few inhibitors of PPIs known, and those that are known are highly non-specific. Little is known about the remaining 16 human PPIs. Inhibitors of a single PPI or small subset of PPIs, would therefore be valuable tools for investigating their functions. I will use fragment-based screening to obtain initial hits to PPIs, and attach those fragment hits to cyclic peptide scaffolds in order to create specific PPI inhibitors.
Cyclic peptides, short amino acid polymers with their N-terminus and C-terminus linked, have the potential to inhibit a range of targets which current drug molecules cannot. Combinatorial library screening of cyclic peptides is well developed, but a fragment-based approach comparable to that available for small molecule drugs has not yet been published. I will develop such a method as part of this work.