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CORDIS

Allostery in Drug Discovery

Project description

Allosteric targeting of proteins: a new class of drugs

Proteins constitute key targets for drug design and modulation, or inhibition of function takes place through small molecules that bind to the primary active site. However, the function of various biological macromolecules may be regulated at alternative distant sites known as allosteric sites. The EU-funded ALLODD project aims to overcome existing challenges in the design of allosteric modulators. Through state-of-the-art technologies, researchers aim to identify and characterise ligands capable of binding to allosteric sites of therapeutically relevant proteins. Considerable effort will also go towards the generation of allosteric antibodies, opening new possibilities in the drug discovery field.

Objective

Most current drugs are designed to bind directly to the primary active sites (also known as orthosteric sites) of their biological targets. Allosteric modulators offer a powerful yet underexploited therapeutic approach. They can elicit a richer variety of biological responses and, since they target less conserved binding sites, higher selectivity and less adverse effects may be obtained (Changeux, Drug Disc Today 2013). This proposal aims to train a new generation of scientists in exploiting the concept of allostery in drug design, putting together a whole array of technologies to identify and characterize allosteric modulators of protein function that will be applied to therapeutically relevant systems. Our approach is based on a combination of experimental and simulation techniques, including fragment Screening with structural characterization (X-ray, NMR, H/D exchange), proteomics (MS/MS), ITC, DNA encoding libraries, Virtual Screening, Molecular Dynamics simulations-based methods, Synthetic Chemistry, and in vitro and cellular assays for the verification of results. It should also be noted that allosteric targeting need not be achieved solely through the design of synthetic small molecules but also can also be reached via conformationally specific allosteric antibodies, which represents an important field of future research. There are already clear examples of monoclonal antibodies that allosterically target ion channels (Lee et al., 2014b), GPCRs (Mukund et al., 2013), and RTKs (De Smet et al., 2014), as well as cytokine and integrin receptors (Rizk et al., 2015; Schwarz et al., 2006).

Coordinator

IDRYMA IATROVIOLOGIKON EREUNON AKADEMIAS ATHINON
Net EU contribution
€ 243 017,64
Address
SORANOU EFESIOU 4
115 27 Athina
Greece

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Region
Αττική Aττική Κεντρικός Τομέας Αθηνών
Activity type
Research Organisations
Links
Total cost
€ 243 017,64

Participants (13)