Orally Active Peptidic Bradykinin B<sub>1</sub> Receptor Antagonists Engineered from a Cyclotide Scaffold for Inflammatory Pain Treatment

Wong, Chi‐Ming; Rowlands, Dewi K.; Wong, C. K.; Lo, Theodore W. C.; Nguyen, Giang Kien Truc; Hy, Li; Tam, James P.

doi:10.1002/ange.201200984

Cited by 73 publications

(91 citation statements)

References 40 publications

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“…This view is supported by a growing number of peptides that appear to be well absorbed within the gastrointestinal tract [5] and examples where cyclic peptides have shown orally-delivered bioactivity in animal models of disease, including inflammatory pain [6] and neuropathic pain [7]. Interestingly, a common structural feature of these reported peptides is a macrocyclic backbone, which is consistent with a study showing that cyclic peptides have improved membrane permeability over their linear counterparts [8].…”

Section: Introductionsupporting

confidence: 65%

Exploring experimental and computational markers of cyclic peptides: Charting islands of permeability

Wang

Northfield

Swedberg

et al. 2015

European Journal of Medicinal Chemistry

108

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An increasing number of macrocyclic peptides that cross biological membranes are being reported, suggesting that it might be possible to develop peptides into orally bioavailable therapeutics; however, current understanding of what makes macrocyclic peptides cell permeable is still limited. Here, we synthesized 62 cyclic hexapeptides and characterized their permeability using in vitro assays commonly used to predict in vivo absorption rates, i.e. the Caco-2 and PAMPA assays. We correlated permeability with experimentally measured parameters of peptide conformation obtained using rapid methods based on chromatography and nuclear magnetic resonance spectroscopy. Based on these correlations, we propose a model describing the interplay between peptide permeability, lipophilicity and hydrogen bonding potential. Specifically, peptides with very high permeability have high lipophilicity and few solvent hydrogen bond interactions, whereas peptides with very low permeability have low lipophilicity or many solvent interactions. Our model is supported by molecular dynamics simulations of the cyclic peptides calculated in explicit solvent, providing a structural basis for the observed correlations. This prospective exploration into biomarkers of peptide permeability has the potential to unlock wider opportunities for development of peptides into drugs.3

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Section: Introductionsupporting

confidence: 65%

Exploring experimental and computational markers of cyclic peptides: Charting islands of permeability

Wang

Northfield

Swedberg

et al. 2015

European Journal of Medicinal Chemistry

108

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“…In fact, cyclotides have been recently used as scaffolds to improve the stability of peptides that have interesting pharmaceutical activities. This grafting introduced peptide sequences into cyclotide loops and resulted in a chimeric molecule that was orally active as bradykinin B1 receptor antagonist in the treatment of chronic inflammatory pain (18). Cyclotides represent a natural combinatorial peptide library and they probe a chemical space that is difficult to target by using small organic molecules (17).…”

Section: Discussionmentioning

confidence: 99%

“…This unique 3D fold confers them intrinsic stability to resist chemical, enzymatic, and thermal degradation (14). Therefore, cyclotides have become attractive tools in chemical biology and drug development (15), for instance as templates for molecular grafting applications (16) as well as for receptor ligand design (17), because they presumably exhibit activity following oral administration (18).…”

mentioning

confidence: 99%

Oral activity of a nature-derived cyclic peptide for the treatment of multiple sclerosis

Thell

Hellinger

Sahin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

116

141

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Multiple sclerosis (MS) is the most common autoimmune disease affecting the central nervous system. It is characterized by autoreactive T cells that induce demyelination and neuronal degradation. Treatment options are still limited and several MS medications need to be administered by parenteral application but are modestly effective. Oral active drugs such as fingolimod have been weighed down by safety concerns. Consequently, there is a demand for novel, especially orally active therapeutics. Nature offers an abundance of compounds for drug discovery. Recently, the circular plant peptide kalata B1 was shown to silence T-cell proliferation in vitro in an IL-2-dependent mechanism. Owing to this promising effect, we aimed to determine in vivo activity of the cyclotide [T20K]kalata B1 using the MS mouse model experimental autoimmune encephalomyelitis (EAE). Treatment of mice with the cyclotide resulted in a significant delay and diminished symptoms of EAE by oral administration. Cyclotide application substantially impeded disease progression and did not exhibit adverse effects. Inhibition of lymphocyte proliferation and the reduction of proinflammatory cytokines, in particular IL-2, distinguish the cyclotide from other marketed drugs. Considering their stable structural topology and oral activity, cyclotides are candidates as peptide therapeutics for pharmaceutical drug development for treatment of T-cell-mediated disorders.cyclic peptides | multiple sclerosis | immunopharmacology | plant natural product | drug discovery

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“…For example, Clark et al (44) demonstrated that it was possible to substitute selected amino acids in loop 5 of kalata B1 to remove intrinsic hemolytic activity but retain the native fold, and later studies on this framework demonstrated efficacy for grafted antiangiogenic sequences (45) and bradykinin antagonists (46). Thongyoo et al (47) changed the specificity of the trypsin inhibitor cyclotide, MCoTI-II, toward other proteases with one to three amino acid substitutions, and Chan et al (48) reported a novel angiogenic agent based on this framework.…”

Section: Obesity Is An Increasingly Important Global Health Problem Tmentioning

confidence: 99%

Design, Synthesis, Structural and Functional Characterization of Novel Melanocortin Agonists Based on the Cyclotide Kalata B1

Eliasen

Daly

Wulff

et al. 2012

Journal of Biological Chemistry

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Background: Cyclotides are useful scaffolds to stabilize bioactive peptides. Results: Four melanocortin analogues of kalata B1 were synthesized. One is a selective MC4R agonist. Conclusion:The analogues retain the native kalata B1 scaffold and introduce a designed pharmacological activity, validating cyclotides as protein engineering scaffolds. Significance: A novel type of melanocortin agonist has been developed, with potential as a drug lead for treating obesity.

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Orally Active Peptidic Bradykinin B₁ Receptor Antagonists Engineered from a Cyclotide Scaffold for Inflammatory Pain Treatment

Cited by 73 publications

References 40 publications

Exploring experimental and computational markers of cyclic peptides: Charting islands of permeability

Exploring experimental and computational markers of cyclic peptides: Charting islands of permeability

Oral activity of a nature-derived cyclic peptide for the treatment of multiple sclerosis

Design, Synthesis, Structural and Functional Characterization of Novel Melanocortin Agonists Based on the Cyclotide Kalata B1

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Orally Active Peptidic Bradykinin B1 Receptor Antagonists Engineered from a Cyclotide Scaffold for Inflammatory Pain Treatment

Cited by 73 publications

References 40 publications

Exploring experimental and computational markers of cyclic peptides: Charting islands of permeability

Exploring experimental and computational markers of cyclic peptides: Charting islands of permeability

Oral activity of a nature-derived cyclic peptide for the treatment of multiple sclerosis

Design, Synthesis, Structural and Functional Characterization of Novel Melanocortin Agonists Based on the Cyclotide Kalata B1

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Product

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Orally Active Peptidic Bradykinin B₁ Receptor Antagonists Engineered from a Cyclotide Scaffold for Inflammatory Pain Treatment