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, Department of Nuclear Medicine, Heidelberg University Hospital, INF 400, 69120 Heidelberg, Department of Nuclear Medicine, Heidelberg University Hospital, INF 400, 69120 Heidelberg
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.
