Forward for ICCP2015 issue of Biopolymers Peptide Science

We welcome readers to this special edition of Biopolymers Peptide Science, which includes a selection of papers based on work presented at the 3rd International Conference on Circular Proteins. The conference was held at the Tangalooma Resort on Moreton Island, Queensland, Australia, from 1st to 4th November 2015. The conference was attended by approximately 70 delegates from 9 countries, including Japan, Canada, USA, Germany, Brazil, Sweden, Austria, Australia and the Philippines. It included talks from more than 44 speakers, along with 28 poster presentations. This special issue comprises 16 articles covering a range of topics in the field of cyclic peptides, spanning the spectrum from discovery to synthesis and biosynthesis, to drug design, bioavailability and nomenclature, as schematically illustrated in Figure 1. This issue is designed around five themes, starting with articles on the discovery of cyclic peptides, followed by studies on their synthesis and applications in drug design and delivery (bioavailability), with a final article focusing on nomenclature. Metaphorically that article closes the ‘cycle’ since nomenclature is intimately connected with discovery. Leading off the issue in the ‘discovery’ section are four articles by Johannes Koehbach, Nicolau da Cunha, Ploypat Niyomploy and Bastian Franke and colleagues, covering the discovery of cyclic peptides from across the world. This section opens with a review of peptidomic and transcriptomic methods for the discovery of cyclic peptides, highlighting some of the techniques that have worked so far, as well as noting the challenges that lie ahead. This review provides an excellent introduction to the next three articles, which are more focused studies that exemplify specific discovery techniques, reporting the discovery of novel Brazilian cyclotides and their genes, the discovery of cyclotides in Southeast Asian plants and the discovery of seed cyclic peptides from Mexican plants. These studies support the general anticipation that many more cyclic peptides await discovery, including probably some with novel topologies (and from organisms other than plants). The ‘synthesis’ section includes three articles from USA and Australia. In the first of these articles. Julio Camarero and colleagues (University of Southern California, USA) describe the successful application of intein-mediated protein splicing for the bacterial expression of SFTI-1. The intein-based approach has so far demonstrated broad versatility for cyclic peptide recombinant expression and thus promises to allow recombinant libraries of cyclic disulfide-rich peptides to be produced and screened. In the next article, Norelle Daly and colleagues (James Cook University, Australia) describe the role of an N-terminal precursor fragment of cyclotides in defining folding. In the final article of this section, Wilfred Van der Donk and colleagues (University of Illinois, USA) describe the lanthionine family of cyclic peptides and investigate their biosynthesis, describing an interesting relationship between the sequence of lanthionine precursors and the stereochemical composition of the mature peptide. The next six articles describe applications of cyclic peptides in drug design. The first of these is from Aline de Araujo and David Fairlie, which reviews recent methods for stapling peptides by cross-linking cysteine side chains. Stapling strategies have attracted increasing attention from drug designers as approaches for restricting conformation and enhancing biopharmaceutical properties. An application of the lactam-bridge stapling approach is described in the article that follows by Sónia Henriques and colleagues, in which the authors report lactam-stapled peptides that target the MDM2 and MDMX proteins involved in cancer pathogenesis. The third article in this section is by Richard Clark and colleagues and describes the use of various linker sequences to connect the N- and C-termini of Vc1.1, a cone snail toxin that has great potential as an analgesic agent. The authors have previously shown that addition of a linker sequence can enhance the stability and activity of Vc1.1, and here show that the linker sequence is also a useful site for expanding functionality. The next two articles from Minying Cai and Victor Hruby provide a summary of cyclization strategies that can be used to modify bioactive peptides, focusing on melanocortin peptides, which are involved in a range of cellular functions, as examples. The final article in this section from Christopher Hipolito reviews the state-of-the-art in terms of combinatorial library based screening approaches, which promise to accelerate the discovery of high affinity cyclic peptide leads. One of the major challenges in the field of peptide drugs is their generally poor bioavailability. In the ‘bioavailability’ section, two articles investigate the bioavailability of cyclic peptides. The first is a review by ourselves (Wang and Craik) on the structural and physicochemical properties of cyclic peptides that are important for passive permeability, a prerequisite for high oral bioavailability. In general, cyclic peptides have demonstrated higher permeability than linear peptides, with chemical/structural/computational strategies for further improving their permeability being recently proposed, but there are still many challenges in the translation of high-affinity peptide leads to orally administered drugs. The article by Erik Melander and colleagues examines methods for the detection of kalata B1 in brain homogenate and plasma, establishing accurate quantification methods that will be useful for studying the bio-distribution of cyclic peptide drugs based on the kalata B1 framework. The final paper in this issue is from Martin Reaney and colleagues, and addresses the issue of cyclic peptide nomenclature. As the conventional nomenclature scheme was designed with linear peptides in mind, this paper takes an exploratory look into challenges of naming cyclic peptides and raises some potential solutions. We take this opportunity to thank all of the participants of the conference for their valuable contributions to this discussion, and also thank the authors of the articles in this issue for their participation and insights. We hope that readers will enjoy the set of articles presented here and that the articles will stimulate further interest in the field of cyclic peptides.

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