Abstract
The lack of specificity of traditional cytotoxic drugs triggers the development of anticancer agents with high selectivity to tumor-specific proteins. The unveiling of target structures such as EGFR or Her2 allows the focused development of novel therapies and has strongly advanced tumor treatment. Tumor-specific high-affinity ligands can be identified by using display techniques such as phage, yeast surface, ribosome and mRNA display. These techniques enable the screening of huge libraries, consequently providing a valuable alternative to rational drug development. In recent years, miniproteins and multicyclic peptides have become the preferred ligands expressed by these libraries. Due to their favorable pharmacokinetics and the ease of their synthesis, peptidic ligands overcome disadvantages of antibody derived therapeutics. Peptides that are structurally defined by a rigid scaffold are ideally suited for the use in display techniques. These molecules feature high stability and excellent affinities while offering the opportunity to randomize partial sequences to be used as binding sites. Structurization of the peptide scaffold can be achieved by different approaches, of which cyclization is one of the most commonly used. The favored cyclization strategies are based on amide or disulfide bridging and the use of synthetic braces or chemical linkers. The use of multicyclic peptides allows the simultaneous presentation of several different binding loops. Semisynthetic approaches enable the introduction of unnatural amino acids, increasing the diversity of the resulting peptide libraries. Given that, miniprotein scaffolds offer a wide range of potential applications and facilitate efficient screening of novel high-affinity ligands to be used in precise diagnosis and highly efficient cancer therapy.
Keywords: Drug development, miniprotein scaffolds, targeted therapy, peptide libraries, display techniques, highaffinity ligands.
Current Medicinal Chemistry
Title:Multicyclic Peptides as Scaffolds for the Development of Tumor Targeting Agents
Volume: 24 Issue: 20
Author(s): Anastasia Loktev, Uwe Haberkorn and Walter Mier*
Affiliation:
- Department of Nuclear Medicine, Heidelberg University Hospital, INF 400, 69120 Heidelberg,Germany
Keywords: Drug development, miniprotein scaffolds, targeted therapy, peptide libraries, display techniques, highaffinity ligands.
Abstract: The lack of specificity of traditional cytotoxic drugs triggers the development of anticancer agents with high selectivity to tumor-specific proteins. The unveiling of target structures such as EGFR or Her2 allows the focused development of novel therapies and has strongly advanced tumor treatment. Tumor-specific high-affinity ligands can be identified by using display techniques such as phage, yeast surface, ribosome and mRNA display. These techniques enable the screening of huge libraries, consequently providing a valuable alternative to rational drug development. In recent years, miniproteins and multicyclic peptides have become the preferred ligands expressed by these libraries. Due to their favorable pharmacokinetics and the ease of their synthesis, peptidic ligands overcome disadvantages of antibody derived therapeutics. Peptides that are structurally defined by a rigid scaffold are ideally suited for the use in display techniques. These molecules feature high stability and excellent affinities while offering the opportunity to randomize partial sequences to be used as binding sites. Structurization of the peptide scaffold can be achieved by different approaches, of which cyclization is one of the most commonly used. The favored cyclization strategies are based on amide or disulfide bridging and the use of synthetic braces or chemical linkers. The use of multicyclic peptides allows the simultaneous presentation of several different binding loops. Semisynthetic approaches enable the introduction of unnatural amino acids, increasing the diversity of the resulting peptide libraries. Given that, miniprotein scaffolds offer a wide range of potential applications and facilitate efficient screening of novel high-affinity ligands to be used in precise diagnosis and highly efficient cancer therapy.
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Cite this article as:
Loktev Anastasia, Haberkorn Uwe and Mier Walter *, Multicyclic Peptides as Scaffolds for the Development of Tumor Targeting Agents, Current Medicinal Chemistry 2017; 24 (20) . https://dx.doi.org/10.2174/0929867324666170316120304
DOI https://dx.doi.org/10.2174/0929867324666170316120304 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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