Special Issue "Discovery and Development of Constrained Peptide Ligands"

A special issue of Biomedicines (ISSN 2227-9059).

Deadline for manuscript submissions: closed (30 June 2018).

Special Issue Editors

Guest Editor
Prof. Dr. Hiroaki Suga

Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
Website | E-Mail
Interests: macrocyclic peptides; genetic code reprogramming; mRNA display
Guest Editor
Dr. Toby Passioura

Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
Website | E-Mail
Interests: macrocyclic peptides; genetic code reprogramming; mRNA display

Special Issue Information

Dear Colleagues,

Constrained peptide ligands often exhibit exquisite target affinity and selectivity, making them appealing candidates for novel drug discovery and development. Unlike smaller molecules, constrained peptides are capable of modulating protein–protein interactions, making them amenable to targeting the so-called “undruggabe” proteome.  Additionally, the intermediate size of constrained peptides relative to small molecules and larger biologics (e.g., antibodies), means that constrained peptides can, in some cases, simultaneously exhibit the benefits of both, with small molecule-like pharmacology and antibody-like specificity and affinity.

We invite research and review papers in the fields of constrained peptide ligand discovery and development, including articles describing macrocyclic peptides, stapled peptides, disulfide constrained peptides, constrained peptide pharmacology and studies of constrained peptide structure–activity relationships.

Prof. Dr. Hiroaki Suga
Dr. Toby Passioura
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • constrained peptide
  • macrocyclic peptide
  • stapled peptide
  • peptide pharmacology
  • peptide structure–activity relationship
  • protein–protein interaction inhibition

Published Papers (7 papers)

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Research

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Open AccessArticle
Pyrrole-Mediated Peptide Cyclization Identified through Genetically Reprogrammed Peptide Synthesis
Biomedicines 2018, 6(4), 99; https://doi.org/10.3390/biomedicines6040099
Received: 28 September 2018 / Revised: 23 October 2018 / Accepted: 24 October 2018 / Published: 30 October 2018
Cited by 1 | PDF Full-text (1458 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Flexible in vitro translation (FIT) was used as a screening method to uncover a new methodology for peptide constraining based on the attack of a nucleophilic side-chain functionality onto an oxidized furylalanine side chain. A set of template peptides, each containing furylalanine as [...] Read more.
Flexible in vitro translation (FIT) was used as a screening method to uncover a new methodology for peptide constraining based on the attack of a nucleophilic side-chain functionality onto an oxidized furylalanine side chain. A set of template peptides, each containing furylalanine as furan-modified amino acid and a nucleophilic residue (Cys, His, Lys, Arg, Ser, or Tyr), was produced through FIT. The translation mixtures were treated with N-bromosuccinimide (NBS) to achieve selective furan oxidation and subsequent MALDI analysis demonstrated Lys and Ser as promising residues for cyclisation. Solid-phase peptide synthesis (SPPS) was used to synthesize suitable amounts of material for further in-depth analysis and characterisation. It was found that in the case of the peptide containing lysine next to a furylalanine residue, a one-pot oxidation and reduction reaction leads to the generation of a cyclic peptide featuring a pyrrole moiety as cyclisation motif, resulting from the attack of the lysine side chain onto the oxidized furylalanine side chain. Structural evidence was provided via NMR and the generality of the methodology was explored. We hereby expand the scope of our previously developed furan-based peptide labeling and crosslinking strategy. Full article
(This article belongs to the Special Issue Discovery and Development of Constrained Peptide Ligands)
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Open AccessArticle
Azasulfurylpeptide Modulation of CD36-Mediated Inflammation Without Effect on Neovascularization
Biomedicines 2018, 6(4), 98; https://doi.org/10.3390/biomedicines6040098
Received: 28 August 2018 / Revised: 26 September 2018 / Accepted: 5 October 2018 / Published: 22 October 2018
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Abstract
Modulation of the cluster of differentiation-36 receptor (CD36) has proven promising for dampening pro-inflammatory macrophage signaling. For example, azapeptides (e.g., 1 and 2) bind CD36 selectively with high affinity, mitigate Toll-like receptor (TLR) agonist-induced overproduction of nitric oxide (NO), and reduce pro-inflammatory [...] Read more.
Modulation of the cluster of differentiation-36 receptor (CD36) has proven promising for dampening pro-inflammatory macrophage signaling. For example, azapeptides (e.g., 1 and 2) bind CD36 selectively with high affinity, mitigate Toll-like receptor (TLR) agonist-induced overproduction of nitric oxide (NO), and reduce pro-inflammatory cytokine and chemokine production in macrophages. Moreover, semicarbazides 1 and 2 inhibit microvascular sprouting mediated through CD36 in the choroid explant. Seeking a selective CD36 modulator that mediated inflammation without influencing neovascularization, a set of azasulfurylpeptides (e.g., 3ae) were synthesized in which the semicarbazide was replaced by an N-aminosulfamide residue using a novel solid-phase approach. Notably, azasulfurylpeptide 3c diminished selectively CD36-mediated TLR-2-triggered inflammatory response without affecting neovascularization. Subtle chemical modification at the peptide backbone from a carbonyl to a sulfuryl residue has had a selective effect on biological activity providing a valuable probe for studying CD36 chemical biology. Full article
(This article belongs to the Special Issue Discovery and Development of Constrained Peptide Ligands)
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Open AccessArticle
Engineering of an Anti-Inflammatory Peptide Based on the Disulfide-Rich Linaclotide Scaffold
Biomedicines 2018, 6(4), 97; https://doi.org/10.3390/biomedicines6040097
Received: 1 July 2018 / Revised: 11 September 2018 / Accepted: 21 September 2018 / Published: 6 October 2018
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Abstract
Inflammatory bowel diseases are a set of complex and debilitating diseases, for which there is no satisfactory treatment. Peptides as small as three amino acids have been shown to have anti-inflammatory activity in mouse models of colitis, but they are likely to be [...] Read more.
Inflammatory bowel diseases are a set of complex and debilitating diseases, for which there is no satisfactory treatment. Peptides as small as three amino acids have been shown to have anti-inflammatory activity in mouse models of colitis, but they are likely to be unstable, limiting their development as drug leads. Here, we have grafted a tripeptide from the annexin A1 protein into linaclotide, a 14-amino-acid peptide with three disulfide bonds, which is currently in clinical use for patients with chronic constipation or irritable bowel syndrome. This engineered disulfide-rich peptide maintained the overall fold of the original synthetic guanylate cyclase C agonist peptide, and reduced inflammation in a mouse model of acute colitis. This is the first study to show that this disulfide-rich peptide can be used as a scaffold to confer a new bioactivity. Full article
(This article belongs to the Special Issue Discovery and Development of Constrained Peptide Ligands)
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Open AccessArticle
Evaluation of Chemical Strategies for Improving the Stability and Oral Toxicity of Insecticidal Peptides
Biomedicines 2018, 6(3), 90; https://doi.org/10.3390/biomedicines6030090
Received: 6 August 2018 / Revised: 22 August 2018 / Accepted: 23 August 2018 / Published: 28 August 2018
Cited by 3 | PDF Full-text (1860 KB) | HTML Full-text | XML Full-text
Abstract
Spider venoms are a rich source of insecticidal peptide toxins. Their development as bioinsecticides has, however, been hampered due to concerns about potential lack of stability and oral bioactivity. We therefore systematically evaluated several synthetic strategies to increase the stability and oral potency [...] Read more.
Spider venoms are a rich source of insecticidal peptide toxins. Their development as bioinsecticides has, however, been hampered due to concerns about potential lack of stability and oral bioactivity. We therefore systematically evaluated several synthetic strategies to increase the stability and oral potency of the potent insecticidal spider-venom peptide ω-HXTX-Hv1a (Hv1a). Selective chemical replacement of disulfide bridges with diselenide bonds and N- to C-terminal cyclization were anticipated to improve Hv1a resistance to proteolytic digestion, and thereby its activity when delivered orally. We found that native Hv1a is orally active in blowflies, but 91-fold less potent than when administered by injection. Introduction of a single diselenide bond had no effect on the susceptibility to scrambling or the oral activity of Hv1a. N- to C-terminal cyclization of the peptide backbone did not significantly improve the potency of Hv1a when injected into blowflies and it led to a significant decrease in oral activity. We show that this is likely due to a dramatically reduced rate of translocation of cyclic Hv1a across the insect midgut, highlighting the importance of testing bioavailability in addition to toxin stability. Full article
(This article belongs to the Special Issue Discovery and Development of Constrained Peptide Ligands)
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Review

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Open AccessReview
The Potential of the Cyclotide Scaffold for Drug Development
Biomedicines 2019, 7(2), 31; https://doi.org/10.3390/biomedicines7020031
Received: 6 April 2019 / Revised: 13 April 2019 / Accepted: 15 April 2019 / Published: 19 April 2019
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Abstract
Cyclotides are a novel class of micro-proteins (≈30–40 residues long) with a unique topology containing a head-to-tail cyclized backbone structure further stabilized by three disulfide bonds that form a cystine knot. This unique molecular framework makes them exceptionally stable to physical, chemical, and [...] Read more.
Cyclotides are a novel class of micro-proteins (≈30–40 residues long) with a unique topology containing a head-to-tail cyclized backbone structure further stabilized by three disulfide bonds that form a cystine knot. This unique molecular framework makes them exceptionally stable to physical, chemical, and biological degradation compared to linear peptides of similar size. The cyclotides are also highly tolerant to sequence variability, aside from the conserved residues forming the cystine knot, and are orally bioavailable and able to cross cellular membranes to modulate intracellular protein–protein interactions (PPIs), both in vitro and in vivo. These unique properties make them ideal scaffolds for many biotechnological applications, including drug discovery. This review provides an overview of the properties of cyclotides and their potential for the development of novel peptide-based therapeutics. The selective disruption of PPIs still remains a very challenging task, as the interacting surfaces are relatively large and flat. The use of the cell-permeable highly constrained polypeptide molecular frameworks, such as the cyclotide scaffold, has shown great promise, as it provides unique pharmacological properties. The use of molecular techniques, such as epitope grafting, and molecular evolution have shown to be highly effective for the selection of bioactive cyclotides. However, despite successes in employing cyclotides to target PPIs, some of the challenges to move them into the clinic still remain. Full article
(This article belongs to the Special Issue Discovery and Development of Constrained Peptide Ligands)
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Open AccessReview
Constrained α-Helical Peptides as Inhibitors of Protein-Protein and Protein-DNA Interactions
Biomedicines 2018, 6(4), 118; https://doi.org/10.3390/biomedicines6040118
Received: 7 August 2018 / Revised: 13 September 2018 / Accepted: 14 September 2018 / Published: 18 December 2018
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Abstract
Intracellular regulatory pathways are replete with protein-protein and protein-DNA interactions, offering attractive targets for therapeutic interventions. So far, most drugs are targeted toward enzymes and extracellular receptors. Protein-protein and protein-DNA interactions have long been considered as “undruggable”. Protein-DNA interactions, in particular, present a [...] Read more.
Intracellular regulatory pathways are replete with protein-protein and protein-DNA interactions, offering attractive targets for therapeutic interventions. So far, most drugs are targeted toward enzymes and extracellular receptors. Protein-protein and protein-DNA interactions have long been considered as “undruggable”. Protein-DNA interactions, in particular, present a difficult challenge due to the repetitive nature of the B-DNA. Recent studies have provided several breakthroughs; however, a design methodology for these classes of inhibitors is still at its infancy. A dominant motif of these macromolecular interactions is an α-helix, raising possibilities that an appropriate conformationally-constrained α-helical peptide may specifically disrupt these interactions. Several methods for conformationally constraining peptides to the α-helical conformation have been developed, including stapling, covalent surrogates of hydrogen bonds and incorporation of unnatural amino acids that restrict the conformational space of the peptide. We will discuss these methods and several case studies where constrained α-helices have been used as building blocks for appropriate molecules. Unlike small molecules, the delivery of these short peptides to their targets is not straightforward as they may possess unfavorable cell penetration and ADME properties. Several methods have been developed in recent times to overcome some of these problems. We will discuss these issues and the prospects of this class of molecules as drugs. Full article
(This article belongs to the Special Issue Discovery and Development of Constrained Peptide Ligands)
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Open AccessReview
Structural Features and Binding Modes of Thioether-Cyclized Peptide Ligands
Biomedicines 2018, 6(4), 116; https://doi.org/10.3390/biomedicines6040116
Received: 12 November 2018 / Revised: 10 December 2018 / Accepted: 11 December 2018 / Published: 13 December 2018
Cited by 3 | PDF Full-text (3367 KB) | HTML Full-text | XML Full-text
Abstract
Macrocyclic peptides are an emerging class of bioactive compounds for therapeutic use. In part, this is because they are capable of high potency and excellent target affinity and selectivity. Over the last decade, several biochemical techniques have been developed for the identification of [...] Read more.
Macrocyclic peptides are an emerging class of bioactive compounds for therapeutic use. In part, this is because they are capable of high potency and excellent target affinity and selectivity. Over the last decade, several biochemical techniques have been developed for the identification of bioactive macrocyclic peptides, allowing for the rapid isolation of high affinity ligands to a target of interest. A common feature of these techniques is a general reliance on thioether formation to effect macrocyclization. Increasingly, the compounds identified using these approaches have been subjected to x-ray crystallographic analysis bound to their respective targets, providing detailed structural information about their conformation and mechanism of target binding. The present review provides an overview of the target bound thioether-closed macrocyclic peptide structures that have been obtained to date. Full article
(This article belongs to the Special Issue Discovery and Development of Constrained Peptide Ligands)
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