Descrizione del progetto
Sviluppare farmaci attingendo a un nuovo spazio chimico
La maggior parte dei farmaci a piccole molecole si lega a enzimi o recettori che hanno tasche di legame ben definite. Tuttavia, è risultato tecnicamente impegnativo generare molecole di piccole dimensioni in grado di ostacolare le interazioni tra proteine o contro le proteine piane. Il progetto TARGET, finanziato dall’UE, si propone di affrontare questo problema tramite una piattaforma automatica in grado di selezionare i ligandi che legano proteine impegnative o incurabili. I ricercatori integreranno raccolte di peptidi codificati geneticamente con quelle di composti chimici per attingere a un enorme spazio chimico e selezionare le combinazioni che legano bersagli proteici difficili. È presumibile che la metodologia di TARGET sosterrà le attività di ricerca future sui farmaci permeabili alle cellule contro proteine impegnative.
Obiettivo
"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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Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-ADG - Advanced GrantIstituzione ospitante
1015 Lausanne
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