Shifting the oligomerization equilibrium of proteins: a novel therapeutic strategy for drug design

Shifting the oligomerization equilibrium of proteins: a novel therapeutic strategy for drug design

Prof. Friedler, of the Hebrew University’s Institute of Chemistry, has developed a novel therapeutic strategy using an innovative concept of shifting the oligomerization equilibrium of proteins for therapeutic purposes. His ‘shiftide’ research has opened new doors in the field of drug design, resulting in a new general methodology for inhibiting or activating protein function for medical purposes.

The aim of the ERC-funded ‘shiftides’ project was to establish a multidisciplinary platform for quantitative biophysical analysis of protein-protein interactions in health and disease as a basis for drug design. The project involved: (1) Analyzing protein-protein interactions at the molecular level in healthy systems; (2) Understanding what goes wrong in disease at the molecular level; (3) Development of drugs that will restore the biological system to its healthy state.

Prof. Assaf Friedler and his team applied this concept of shifting the oligomerization equilibrium of proteins as a therapeutic strategy. Many disease-related proteins are in equilibrium between oligomeric states (e.g., dimer and tetramer). Some of these states are active and some are inactive. The “shiftides” concept he developed enables peptides that shift the oligomerization equilibrium of a protein to modulate its activity, introducing a new, widely applicable methodology for drug design. He has demonstrated its feasibility both for: (1) Inhibiting a protein by binding preferentially to the inactive oligomeric state and shifting the oligomerization equilibrium of the protein towards it; and (2) Activating a protein by binding preferentially to the active oligomeric state and shifting the oligomerization equilibrium towards it.

The proof of concept was established on the HIV-1 integrase protein (IN). This viral enzyme catalyzes the integration of the HIV-1 cDNA into the genome of the infected cells. IN is an attractive target for anti-HIV drug design. Prof. Friedler and his team developed several peptides that bind specifically to the tetrameric state of IN and inhibit its activity as well as HIV-1 replication in cells and in a mouse model.

Prof. Assaf Friedler received a European Research Council starting grant of 1,250,000 euro for this research in the first call of the ERC scheme in 2007.


Prof. Friedler