Descripción del proyecto
Desarrollo de fármacos aprovechando un nuevo espacio químico
La mayoría de fármacos de molécula pequeña se adhieren a enzimas o proteínas receptoras con hendiduras de unión bien definidas. Sin embargo, desde un punto de vista técnico, ha resultado difícil generar moléculas pequeñas que interfieran en las interacciones entre proteínas o que actúen contra proteínas planas. El proyecto TARGET, financiado con fondos europeos, se propone abordar este problema mediante una plataforma automática capaz de identificar ligandos que se adhieran a proteínas difíciles o no modulables. Los investigadores combinarán bibliotecas de péptidos codificados genéticamente con bibliotecas de compuestos químicos para aprovechar un enorme espacio químico e identificar las combinaciones que se adhieren a proteínas diana difíciles. La metodología de TARGET debería impulsar el futuro descubrimiento de fármacos capaces de penetrar en las células para combatir proteínas difíciles.
Objetivo
"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.
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Ámbito científico
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Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
1015 Lausanne
Suiza