Journal article
Dual-display of small molecules enables the discovery of ligand pairs and facilitates affinity maturation.
- Wichert M Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland.
- Krall N Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland.
- Decurtins W Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland.
- Franzini RM Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland.
- Pretto F Philochem AG, 8112 Otelfingen, Switzerland.
- Schneider P Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland.
- Neri D Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland.
- Scheuermann J Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland.
- 2015-02-21
Published in:
- Nature chemistry. - 2015
Animals
Carbonic Anhydrases
DNA
Drug Discovery
Horseradish Peroxidase
Ligands
Mice
Mice, Inbred BALB C
Mice, Nude
Nucleic Acid Hybridization
Orosomucoid
Small Molecule Libraries
Streptavidin
English
In contrast to standard fragment-based drug discovery approaches, dual-display DNA-encoded chemical libraries have the potential to identify fragment pairs that bind simultaneously and benefit from the chelate effect. However, the technology has been limited by the difficulty in unambiguously decoding the ligand pairs from large combinatorial libraries. Here we report a strategy that overcomes this limitation and enables the efficient identification of ligand pairs that bind to a target protein. Small organic molecules were conjugated to the 5' and 3' ends of complementary DNA strands that contain a unique identifying code. DNA hybridization followed by an inter-strand code-transfer created a stable dual-display DNA-encoded chemical library of 111,100 members. Using this approach we report the discovery of a low micromolar binder to alpha-1-acid glycoprotein and the affinity maturation of a ligand to carbonic anhydrase IX, an established marker of renal cell carcinoma. The newly discovered subnanomolar carbonic anhydrase IX binder dramatically improved tumour targeting performance in vivo.
- Language
-
- English
- Open access status
- closed
- Identifiers
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- DOI 10.1038/nchem.2158
- PMID 25698334
- Persistent URL
- https://folia.unifr.ch/global/documents/217340
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