Protein-Protein Interactions - From Inhibition to Degradation
George Burslem, Ph.D.
Postdoctoral Research Fellow
Department of Molecular, Cellular and Developmental Biology
CBC Faculty Candidate
Protein-protein interactions (PPIs) are implicated in virtually all biological pathways and provide a myriad of opportunities for chemical modulation. Exploration of techniques for both the abrogation and enactment of PPIs may provide potential methods for therapeutic intervention as well as enhanced understanding of biological systems.
Imitation of a protein can provide an attractive technique for the inhibition of PPIs, particularly in the context of α-helix mediated PPIs. Using the example of the HIF-1α/p300 PPI, a variety of proteomimetic approaches will be described including the development of small molecule helix mimetics, small molecule-peptide hybrids, phage-display derived peptides and affimer proteins as PPI modulators.
Alternatively, chemical approaches can be employed to induce ectopic protein-protein interactions. These artificial interactions are crucial for the activity of compounds which induce targeted protein degradation. Work exploring the applications and requirements of “molecular glue” compounds and heterobifunctional compounds (Proteolysis Targeting Chimera) will be described.