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ScienceDirect Editorial overview: Next generation therapeutics: Creating and exploiting the chemistry of large numbers Jo¨rg Scheuermann and Dario Neri Current Opinion in Chemical Biology 2015, 26:iv–v For a complete overview see the Issue Available online 15th April 2015 http://dx.doi.org/10.1016/j.cbpa.2015.03.014 1367-5931/# 2015 Elsevier Ltd. All rights reserved.
Jo¨rg Scheuermann ETH Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, 8093 Zurich, Switzerland e-mail: [email protected] Jo¨rg Scheuermann studied Chemistry in Heidelberg (Germany) and at ETH Zurich (Switzerland). After his PhD on the isolation of novel binding molecules to the EDB domain of fibronectin, he chose to stay with Dario Neri and co-developed DNA-encoded chemical library technology. Currently, he is finishing his habilitation in this field.
Dario Neri ETH Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, 8093 Zurich, Switzerland e-mail: [email protected] Dario Neri studied Chemistry in Pisa (Italy) and at ETH Zurich (Switzerland). After postdoctoral research activities at the Medical Research Council, Cambridge (UK), he returned to ETH Zurich as a professor in 1996. His research focuses on strategies for the targeted delivery of therapeutic effectors to sites of disease and the development of DNA-encoded chemical libraries. He is author of over 300 peer-reviewed publications and co-founder of Philogen, a Swiss-Italian biotech company which has brought several antibody drugs into clinical development programs.
This edition of Current Opinions in Chemical Biology, dedicated to NextGeneration Therapeutics, features a series of review articles with a specific focus on large combinatorial libraries and their impact on drug discovery. It also includes a review dedicated on high-throughput screening (HTS) from an industry’s perspective (M. Wigglesworth and co-workers from AstraZeneca). Modern technologies, however, have made it possible to go beyond conventional HTS procedures for hit discovery applications. For over two decades, very large collections of polypeptides (e.g. antibodies) have been synthesized and screened, allowing the isolation of binders against virtually any target protein of interest. In addition, the advent of DNA-encoded chemical libraries has facilitated the synthesis and screening of collections of small molecules of unprecedented size. The success of DNA-encoded chemical libraries and of methods for the selection of binding polypeptides (e.g. phage display) out of large combinatorial libraries relies on a basic principle, which is common to both procedures. Both approaches feature a direct linkage between a binding ‘phenotype’ (e.g. a molecule capable of interacting with a target protein of interest) and a corresponding ‘genotype’ (i.e. an amplifiable nucleic acid sequence allowing the identification of rare binders within a large pool of candidate molecules) (Figure 1). The encoding of polypeptides or of chemical compounds allow to play the ‘Chemistry of Large Numbers’, to use an expression frequently mentioned by Prof. Richard Lerner, one of the pioneers in this research field and the author of one of the reviews featured in this volume. Richard Lerner has done fundamental work both in the field of antibody engineering and in the area of DNA-encoded chemical libraries. His most recent contribution focused on the in vivo selection of antibodies, capable of reprogramming cell fate development. A historic account on antibody phage display libraries is presented in the review article of John McCafferty, who co-authored with Sir Gregory Winter a seminal paper on antibody phage display technology. Sir Gregory Winter and Christian Heinis have contributed a review article, which surveys innovative methods for the construction and use of large combinatorial libraries of chemically modified peptides. This work represents the latest addition to the area of Protein Engineering, which Sir Gregory Winter and collaborators helped establish as a scientific discipline
Current Opinion in Chemical Biology 2015, 26:iv–v
www.sciencedirect.com
Editorial overview Scheuermann and Neri v
Figure 1
(a)
(b)
(c)
Target protein
Target protein
Target protein
Antibody phenotype
Cyclic peptide phenotype
Plasmid genotype
Plasmid genotype
Small organic molecule phenotype DNA tag genotype
Current Opinion in Chemical Biology
Three display technologies capable of linking a displayed phenotype (i.e. an antibody, a peptide or a small-molecule) to an encoding genotype (e.g. a bacteriophage, a plasmid, or neat DNA). Schematic representations of (a) phage-display technology, (b) cyclic peptide display technology, and (c) DNA-encoded chemical library technology.
over 30 years ago. Cyclic peptides, comprising unnatural aminoacids, are also covered in a review article contributed by Hiroaki Suga and collaborators. Their technology allows the construction and selection of peptide libraries, containing over 1012 library members. Using their innovative peptide-based technologies, high-affinity ligands to proteins of pharmaceutical interest have been described both by the Winter/Heinis groups and by the Suga group. Many review articles in this volume are devoted to different aspects of DNA-encoded chemical libraries. Various approaches can be considered, when using DNA as a tool for the encoding of individual library members. On one hand, individual molecules can be attached to DNA oligonucleotides serving as amplifiable identification barcodes. Some of the most relevant methods in the field are covered in the reviews of David Liu and coworkers, Xiaoyu Li and coworkers, Nils Hansen and coworkers, William Connors and coworkers, and Anthony Keefe and coworkers. Alternatively, two sets
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of molecules can be coupled to complementary DNA strands, leading to ‘Dual-pharmacophore chemical libraries’. Such libraries can be encoded by DNA (as outlined in the review article contributed by us, Scheuermann and Neri) or by PNA, as described in the review contributed by Nicolas Winssinger and coworkers. Examples for the advantageous in vivo properties of targeted small-molecules, e.g. derived from DNAencoded chemical library technology, are presented in the reviews of Wichert and Krall, and of Samain and Casi. We hope that the compilation of some of the most recent work in the field of encoded combinatorial libraries of antibodies, peptides and small organic molecules may be of interest to the readers, who will find in a single volume a timely account of some of the most relevant and modern developments in the field. We believe that efficient methods to play the ‘chemistry of large numbers’ may greatly facilitate the discovery of novel therapeutic agents and of tools for Chemical Biology research.
Current Opinion in Chemical Biology 2015, 26:iv–v
ScienceDirect Editorial overview: Next generation therapeutics: Creating and exploiting the chemistry of large numbers Jo¨rg Scheuermann and Dario Neri Current Opinion in Chemical Biology 2015, 26:iv–v For a complete overview see the Issue Available online 15th April 2015 http://dx.doi.org/10.1016/j.cbpa.2015.03.014 1367-5931/# 2015 Elsevier Ltd. All rights reserved.
Jo¨rg Scheuermann ETH Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, 8093 Zurich, Switzerland e-mail: [email protected] Jo¨rg Scheuermann studied Chemistry in Heidelberg (Germany) and at ETH Zurich (Switzerland). After his PhD on the isolation of novel binding molecules to the EDB domain of fibronectin, he chose to stay with Dario Neri and co-developed DNA-encoded chemical library technology. Currently, he is finishing his habilitation in this field.
Dario Neri ETH Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, 8093 Zurich, Switzerland e-mail: [email protected] Dario Neri studied Chemistry in Pisa (Italy) and at ETH Zurich (Switzerland). After postdoctoral research activities at the Medical Research Council, Cambridge (UK), he returned to ETH Zurich as a professor in 1996. His research focuses on strategies for the targeted delivery of therapeutic effectors to sites of disease and the development of DNA-encoded chemical libraries. He is author of over 300 peer-reviewed publications and co-founder of Philogen, a Swiss-Italian biotech company which has brought several antibody drugs into clinical development programs.
This edition of Current Opinions in Chemical Biology, dedicated to NextGeneration Therapeutics, features a series of review articles with a specific focus on large combinatorial libraries and their impact on drug discovery. It also includes a review dedicated on high-throughput screening (HTS) from an industry’s perspective (M. Wigglesworth and co-workers from AstraZeneca). Modern technologies, however, have made it possible to go beyond conventional HTS procedures for hit discovery applications. For over two decades, very large collections of polypeptides (e.g. antibodies) have been synthesized and screened, allowing the isolation of binders against virtually any target protein of interest. In addition, the advent of DNA-encoded chemical libraries has facilitated the synthesis and screening of collections of small molecules of unprecedented size. The success of DNA-encoded chemical libraries and of methods for the selection of binding polypeptides (e.g. phage display) out of large combinatorial libraries relies on a basic principle, which is common to both procedures. Both approaches feature a direct linkage between a binding ‘phenotype’ (e.g. a molecule capable of interacting with a target protein of interest) and a corresponding ‘genotype’ (i.e. an amplifiable nucleic acid sequence allowing the identification of rare binders within a large pool of candidate molecules) (Figure 1). The encoding of polypeptides or of chemical compounds allow to play the ‘Chemistry of Large Numbers’, to use an expression frequently mentioned by Prof. Richard Lerner, one of the pioneers in this research field and the author of one of the reviews featured in this volume. Richard Lerner has done fundamental work both in the field of antibody engineering and in the area of DNA-encoded chemical libraries. His most recent contribution focused on the in vivo selection of antibodies, capable of reprogramming cell fate development. A historic account on antibody phage display libraries is presented in the review article of John McCafferty, who co-authored with Sir Gregory Winter a seminal paper on antibody phage display technology. Sir Gregory Winter and Christian Heinis have contributed a review article, which surveys innovative methods for the construction and use of large combinatorial libraries of chemically modified peptides. This work represents the latest addition to the area of Protein Engineering, which Sir Gregory Winter and collaborators helped establish as a scientific discipline
Current Opinion in Chemical Biology 2015, 26:iv–v
www.sciencedirect.com
Editorial overview Scheuermann and Neri v
Figure 1
(a)
(b)
(c)
Target protein
Target protein
Target protein
Antibody phenotype
Cyclic peptide phenotype
Plasmid genotype
Plasmid genotype
Small organic molecule phenotype DNA tag genotype
Current Opinion in Chemical Biology
Three display technologies capable of linking a displayed phenotype (i.e. an antibody, a peptide or a small-molecule) to an encoding genotype (e.g. a bacteriophage, a plasmid, or neat DNA). Schematic representations of (a) phage-display technology, (b) cyclic peptide display technology, and (c) DNA-encoded chemical library technology.
over 30 years ago. Cyclic peptides, comprising unnatural aminoacids, are also covered in a review article contributed by Hiroaki Suga and collaborators. Their technology allows the construction and selection of peptide libraries, containing over 1012 library members. Using their innovative peptide-based technologies, high-affinity ligands to proteins of pharmaceutical interest have been described both by the Winter/Heinis groups and by the Suga group. Many review articles in this volume are devoted to different aspects of DNA-encoded chemical libraries. Various approaches can be considered, when using DNA as a tool for the encoding of individual library members. On one hand, individual molecules can be attached to DNA oligonucleotides serving as amplifiable identification barcodes. Some of the most relevant methods in the field are covered in the reviews of David Liu and coworkers, Xiaoyu Li and coworkers, Nils Hansen and coworkers, William Connors and coworkers, and Anthony Keefe and coworkers. Alternatively, two sets
www.sciencedirect.com
of molecules can be coupled to complementary DNA strands, leading to ‘Dual-pharmacophore chemical libraries’. Such libraries can be encoded by DNA (as outlined in the review article contributed by us, Scheuermann and Neri) or by PNA, as described in the review contributed by Nicolas Winssinger and coworkers. Examples for the advantageous in vivo properties of targeted small-molecules, e.g. derived from DNAencoded chemical library technology, are presented in the reviews of Wichert and Krall, and of Samain and Casi. We hope that the compilation of some of the most recent work in the field of encoded combinatorial libraries of antibodies, peptides and small organic molecules may be of interest to the readers, who will find in a single volume a timely account of some of the most relevant and modern developments in the field. We believe that efficient methods to play the ‘chemistry of large numbers’ may greatly facilitate the discovery of novel therapeutic agents and of tools for Chemical Biology research.
Current Opinion in Chemical Biology 2015, 26:iv–v
