Cyclic peptides on a merry-go-round; towards drug design Anthi Tapeinou1, Minos-Timotheos Matsoukas2, Carmen Simal1 and Theodore Tselios1,* 1 2
Department of Chemistry, University of Patras, 26500, Patras, Greece
Laboratory of Computational Medicine, Faculty of Medicine, Autonomous University of Barcelona, 08193, Bellaterra, Spain
*
Corresponding author: Theodore Tselios, email:
[email protected], tel: +302610997905
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/bip.22669 © 2015 Wiley Periodicals, Inc. This article is protected by copyright. All rights reserved.
Biopolymers: Peptide Science
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Cyclic peptides on merry-go-round; towards drug design Anthi Tapeinou, Minos-Timotheos Matsoukas, Carmen Simal and Theodore Tselios*
Abstract
Peptides and proteins are attractive initial leads for the rational design of bioactive molecules. Several natural cyclic peptides have recently emerged as templates for drug design due to their resistance to chemical or enzymatic hydrolysis and high selectivity to receptors. The development of practical protocols that mimic the power of nature’s strategies remains paramount for the advancement of novel peptide-based drugs. The de novo design of peptide mimetics (non-peptide molecules or cyclic peptides) for the synthesis of linear or cyclic peptides has enhanced the progress of therapeutics and diverse areas of science and technology. In the case of metabolically unstable peptide ligands, the rational design and synthesis of cyclic peptide analogues has turned into an alternative approach for improved biological activity.
Keywords: cyclic peptides, solid-phase peptide synthesis, rational drug design.
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John Wiley & Sons, Inc. This article is protected by copyright. All rights reserved.
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Biopolymers: Peptide Science
Introduction Peptides constitute one of the most promising platforms for drug development due to their biocompatibility, chemical diversity, and resemblance to proteins.1 Inspired by the protein assembly in biological systems, a large number of peptides have been designed using different amino acids and sequences, while forming unique folded structures (‘fold-on-binding’) and providing a broad spectrum of physiological and biological activities.2 In this regard, peptides have triggered applications that currently range from drug discovery3 to nanomaterials;4 such as nanofibers for biomedical purposes, tissue engineering,5 vaccines,6 and medical imaging technologies,7 among others. The computer-aided drug design approaches8 along with efficient and economic peptide synthesis have contributed to revitalize peptide-based drugs in the current pharmaceutical market. Innovative tools for the identification and characterization of new protein binding sites9 (‘PPi’ protein-protein interaction) have also evoked the discovery and optimization of novel drugs via protein-protein interaction specificities.10 Notably, these binding areas in PPis are regularly nonadjacent, and the interaction interfaces are often found in exposed loop regions.11 These regions are less accessible by small-molecule-based therapeutics (MW
