Final Report Summary - SHIFTIDES (Shifting the oligomerization equilibrium of proteins: a novel therapeutic strategy) The aim of the shiftides project is to establish a multidisciplinary platform for quantitative biophysical analysis of protein-protein interactions in health and disease as a basis for drug design: (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 conditions. We apply the above approach to establish the concept of shifting the oligomerization equilibrium of proteins as a therapeutic strategy. Many disease-related proteins are in equilibrium between several oligomeric states (e.g. dimer and tetramer). Some of these states are active and some are inactive. We developed the “shiftides” concept: peptides that shift the oligomerization equilibrium of a protein to modulate its activity, as a new and widely applicable methodology for drug design. We have demonstrated the feasibility of this concept for: (1) inhibiting a protein by binding preferentially to the inactive oligomeric state and shifting the oligomerization equilibrium of the protein towards it; (2) Activating a protein by binding preferentially to the active oligomeric state and shifting the oligomerization equilibrium towards it. Some of the specific proteins we study are:1. 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. We 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 mouse model.2. The tumor suppressor p53: This protein is at the centre of the major anti-cancer defence mechanism in the cell. It is active as a tetramer in the nucleus and exported to the cytoplasm as a dimer for degradation. Activating p53 by shifting its oligomerization equilibrium from the inactive dimer to the active tetramer is an important goal in cancer therapy. We developed peptides that stabilize the p53 tetramer. Such peptides have the potential to serve as anti-cancer lead compounds.3. Other cancer-related oligomeric proteins, e.g. non-muscle myosin II-CWithin the frame of the project, we established the shiftide concept making it a general method applicable for every disease-related protein that has several oligomeric forms. Our project opened new doors in the field of drug design, resulting in a general new methodology to affect protein function for medical purposes.
