Project description
Drug development by tapping into a new chemical space
Most small molecule drugs bind to enzymes or receptor proteins that have well-defined binding pockets. However, generating small molecules that interfere with protein-protein interactions or against flat proteins has proved technically challenging. The EU-funded TARGET project aims to address this problem through an automatic platform capable of identifying ligands that bind to challenging or undruggable proteins. Researchers will combine genetically encoded peptide libraries with chemical compound libraries to tap into an enormous chemical space and identify combinations that bind to challenging protein targets. The TARGET methodology is expected to support future discovery efforts of cell permeable drugs against challenging proteins.
Objective
"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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Funding Scheme
ERC-ADG - Advanced GrantHost institution
1015 Lausanne
Switzerland