Dr. Assaf Friedler

Abstract:

Protein-Protein Interactions (PPI) mediate numerous processes in cells in health and disease. However, it is extremely challenging to make them drug targets. This is especially true for intrinsically disordered proteins (IDPs). The research in our lab focuses on using peptides for the quantitative biophysical and structural analysis of PPI. Based on this, we develop lead peptides that modulate PPI for therapeutic purposes. Our latest research directions include:

1. Control of condensation and aggregation of proteins by multiphosphorylation: Specific phosphorylation patterns dictate the activity and interactions of many proteins. We developed new methods for rapid and efficient of peptide libraries with distinct multi-phosphorylation patterns. This enables systematic studying at the level of isolated protein domains. We used these tools to elucidate how multi-phosphorylation regulates the self-assembly and activity of two IDPs: the cancer-related APC protein and the neurodegenerative diseases-related Tau protein.
2. 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 structured and disordered parts, which target both structured and disordered hot spots at the same protein.  The approach is demonstrated for inhibiting the anti-apoptotic iASPP protein.  
3. Specific targeting of cancer cells by a designed peptide: We developed a peptide that specifically targets cancer cells and kills them by activating cell death pathways. The peptide is derived from the NAF-1 protein and acts by selectively penetrating the plasma membrane of cancer cells and targeting their mitochondria-ER network. 
4. Inhibiting protein aggregation in disease: Strategies to inhibit aggregation in disease usually focus on highly specific inhibitors for one hotspot but have not made a clinical impact yet. We developed a systematic 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.