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Shifting the oligomerization equilibrium of proteins: a novel therapeutic strategy

Objectif

The aim of my 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. My team will apply this approach to establish the concept of shifting the oligomerization equilibrium of proteins as a therapeutic strategy. I will expand the concepts of allosteric inhibitors and chemical chaperones, and develop the “shiftides”: peptides that shift the oligomerization equilibrium of a protein to modulate its activity, as a new and widely applicable methodology for drug design. I will apply 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; I have demonstrated the feasibility of this approach and developed promising anti-HIV peptides that inhibit the HIV-1 integrase and consequently HIV-1 replication in cells by shifting the integrase oligomerization equilibrium from the active dimer to the inactive tetramer. My team will further develop these peptides, and apply the same approach to inhibit the HIV proteins reverse transcriptase and protease; (2) Activating a protein by binding preferentially to the active oligomeric state and shifting the oligomerization equilibrium towards it: This will be applied for activation of the tumor suppressor p53, by shifting its oligomerization equilibrium from the inactive dimer to the active tetramer. Such shiftides will serve as anti-cancer lead compounds. My project will open new doors in the field of drug design, and at the end of the five-year period will result in a general new methodology to affect protein function for medical purposes.

Appel à propositions

ERC-2007-StG
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Régime de financement

ERC-SG - ERC Starting Grant

Institution d’accueil

THE HEBREW UNIVERSITY OF JERUSALEM
Contribution de l’UE
€ 1 250 000,00
Adresse
EDMOND J SAFRA CAMPUS GIVAT RAM
91904 Jerusalem
Israël

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Type d’activité
Higher or Secondary Education Establishments
Chercheur principal
Assaf Friedler (Dr.)
Contact administratif
Eran Vardi (Dr.)
Liens
Coût total
Aucune donnée

Bénéficiaires (1)