Projektbeschreibung
Allosterische Targetproteine als neue Wirkstoffklasse
Proteine sind wichtige Zielstrukturen für die Arzneimittelentwicklung und Modulation von Prozessen. Niedermolekulare Inhibitoren binden dabei an das primäre aktive Zentrum. Bei mehreren biologischen Makromolekülen kann die Funktion auch über andere, entferntere (allosterische) Bindungsstellen reguliert werden. Das EU-finanzierte Projekt ALLODD soll bestehende Probleme bei der Entwicklung allosterischer Modulatoren ausräumen und mit modernsten Technologien Liganden identifizieren und charakterisieren, die an allosterische Bindungsstellen therapeutisch relevanter Proteine binden. Intensiv wird auch an der Erzeugung allosterischer Antikörper geforscht, was neue Wege in der Wirkstoffforschung eröffnet.
Ziel
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).
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MSCA-ITN - Marie Skłodowska-Curie Innovative Training Networks (ITN)Koordinator
115 27 Athina
Griechenland