Projektbeschreibung
Chemical Space: Potenzial für die Arzneistoffforschung
Die meisten pharmakologischen Moleküle binden an Enzyme oder Rezeptorproteine, die wohldefinierte Bindungstaschen besitzen. Eine technische Herausforderung ist allerdings noch die Erzeugung niedermolekularer Wirkstoffe, die in Proteininteraktion eingreifen oder gegen Proteine mit flacher Oberfläche wirken. Das EU-finanzierte Projekt TARGET entwickelt eine automatisierte Plattform zur Identifizierung von Liganden, die an komplexe oder für Wirkstoffe unzugängliche Proteine binden. Indem Bibliotheken biologischer Substanzen (Peptide) mit chemischen Substanzbibliotheken kombiniert werden, soll der Chemical Space weiter erschlossen werden, um Kombinationen zu identifizieren, die an komplexe Proteintargets binden. Die Methode von TARGET könnte künftige Forschungen an zellgängigen Arzneistoffen unterstützen, die auf komplexe Proteine wirken.
Ziel
"Genome sequencing combined with powerful new research technologies has greatly expanded the number of potential drug targets, offering enormous opportunities to address unmet medical needs. However, for proteins with flat, featureless surfaces or for protein-protein interactions, it has been difficult to impossible to generate ligands based on classical small molecules, hindering their evaluation as targets and the development of drugs.
Herein, we propose a new method and its application for targeting the so-called ""undruggable"" proteins by tapping into a new chemical space, generated by ""merging"" biological and chemical compound libraries. In brief, millions of short cyclic peptides (4–6 amino acids) genetically encoded by phage display (generated with methods we established previously) will be expanded by combinatorially attaching via lateral groups > 1000 different chemical fragments in separate wells of microwell plates. We will develop a strategy that combines the elements of i) automation, ii) liquid transfer by acoustic dispensing, iii) single-round phage display panning, iv) ""phage PCR"" and a primer coding strategy, v) next-generation sequencing (NGS) and vi) computational sequence analysis to perform phage display selections with a library comprising > 1000 non-natural building blocks.
We expect that this technology will deliver ligands to challenging proteins and facilitate their evaluation as drug targets. The ligands are kept small on purpose, below one kDa, and the polarity is limited so that they are more likely to be cell permeable and so they may directly serve as leads for the generation of oral drugs.
"
Wissenschaftliches Gebiet
Schlüsselbegriffe
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-ADG - Advanced GrantGastgebende Einrichtung
1015 Lausanne
Schweiz