Organic Chemistry Seminar: Peptide Inhibitors of Protein-Protein Interactions

Abstract:

Protein-Protein Interactions (PPI) mediate most of the vital processes in cells and are involved in numerous diseases. However, it is extremely challenging to make them drug targets. The research in our lab focuses on using peptides for the quantitative biophysical and structural analysis of PPI in health and disease. Based on this, we develop lead peptides that modulate PPI for therapeutic purposes. In my talk I will give three recent examples for peptides developed in our lab, which target different types of PPI.

1. Inhibiting structured and disordered domains simultaneously: We developed a strategy for inhibiting the structured and disordered hot spots of an interaction using chimeric peptides that contain both cyclic structured and disordered parts., which target both disordered and structured hot spots at the same protein.  The approach is demonstrated for peptide inhibitors of the interactions of the anti-apoptotic iASPP protein. (1) 

2. Specific targeting of cancer cells by a designed peptide: We developed a peptide that specifically targets cancer cells and selectively kills them by activating cell death pathways. The peptide is derived from the NAF-1 protein, a human iron-sulfur cluster containing protein that is anchored to the mitochondrial-ER membrane network. The peptide does so by selectively penetrating the plasma membrane of cancer cells and targeting their mitochondria-ER network. (2) 

3. Inhibiting protein aggregation in disease: Protein aggregation correlates with a large number of human diseases. Strategies to inhibit aggregation usually aim to design highly specific inhibitors for one hotspot or protein conformation but have not made a clinical impact yet. We developed a systematic rational design approach for designing chaperone-like peptides targeting early aggregation stages populated by dynamic precursors, before a mechanistic differentiation takes place. Peptides designed using this strategy inhibited aggregation of disease-related proteins that aggregate in completely different pathways and may serve as general lead compounds against numerous protein aggregation diseases.

1.    Mayer et al (2022), ACS Chemical Biology

2.    Sohn et al (2022), Chem Sci 

3.    Garfagnini et al (2022) BioRxiv
 

Event Organizer: Dr. Muhammad Jbara