Improving on Nature: Making a Cyclic Heptapeptide Orally Bioavailable

Nielsen, Daniel S.; Hoang, Huy N.; Lohman, Rink-Jan; Hill, Timothy A.; Lucke, Andrew J.; Craik, David J.; Edmonds, David J.; Griffith, David A.; Rotter, Charles J.; Ruggeri, Roger B.; Price, David A.; Liras, Spiros; Fairlie, David P.

doi:10.1002/anie.201405364

Cited by 126 publications

(181 citation statements)

References 29 publications

(9 reference statements)

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“…In addition to the basic amine resulting from the rearrangement, the crystal structure of iso-CSA shows two exposed amide NH groups that are involved in intermolecular hydrogen bonds in the unit cell [51]. The crystal structure of iso-CSA also suggests that the Bmt side chain is capable of folding over the secondary amine, possibly lowering the desolvation energy by steric shielding [52,53]. However, the low-dielectric solution conformation of iso-CSA may be closer to that of the parent compound, and the 2° amine may not have a large negative impact on permeability since its calculated p K a of 7.8 [54] suggests that a significant portion of the neutral species exists at pH 7.4.…”

Section: Resultsmentioning

confidence: 99%

Beyond cyclosporine A: conformation-dependent passive membrane permeabilities of cyclic peptide natural products

Ahlbach

Lexa

Bockus

et al. 2015

Future Medicinal Chemistry

145

141

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Many cyclic peptide natural products are larger and structurally more complex than conventional small molecule drugs. Although some molecules in this class are known to possess favorable pharmacokinetic properties, there have been few reports on the membrane permeabilities of cyclic peptide natural products. Here, we present the passive membrane permeabilities of 39 cyclic peptide natural products, and interpret the results using a computational permeability prediction algorithm based on their known or calculated 3D conformations. We found that the permeabilities of these compounds, measured in a parallel artificial membrane permeability assay, spanned a wide range and demonstrated the important influence of conformation on membrane permeability. These results will aid in the development of these compounds as a viable drug paradigm.

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Section: Resultsmentioning

confidence: 99%

Beyond cyclosporine A: conformation-dependent passive membrane permeabilities of cyclic peptide natural products

Ahlbach

Lexa

Bockus

et al. 2015

Future Medicinal Chemistry

145

141

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“…Specifically, structural studies of cell-permeable peptides have suggested that steric occlusion of polar groups and internal hydrogen bonding can lead to increased permeability [39,40]. Recognizing that hydrogen bonding potential is heavily dependent on conformation, we explored whether structural tools that can experimentally probe the hydrogen bond network can also be used as biomarkers of peptide permeability.…”

Section: Discussionmentioning

confidence: 99%

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

Wang

Northfield

Swedberg

et al. 2015

European Journal of Medicinal Chemistry

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106

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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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“…Heterocyclization further increases the hydrophobicity of the natural product. 577, 578 Additional modifications such prenylation or methylation also decreases polarity as well as the number of hydrogen bond donors. 572, 578 Although rules are emerging for predicting the bioavailability of macrocycles, 574, 579 it appears that the conformation of the macrocycle is an important consideration.…”

Section: Cyanobactinsmentioning

confidence: 99%

YcaO-Dependent Posttranslational Amide Activation: Biosynthesis, Structure, and Function

et al. 2017

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With advances in sequencing technology, uncharacterized proteins and domains of unknown function (DUFs) are rapidly accumulating in sequence databases and offer an opportunity to discover new protein chemistry and reaction mechanisms. The focus of this review, the formerly enigmatic YcaO superfamily (DUF181), has been found to catalyze a unique phosphorylation of a ribosomal peptide backbone amide upon attack by different nucleophiles. Established nucleophiles are the side chains of Cys, Ser, and Thr which gives rise to azoline/azole biosynthesis in ribosomally synthesized and posttranslationally modified peptide (RiPP) natural products. However, much remains unknown about the potential for YcaO proteins to collaborate with other nucleophiles. Recent work suggests potential in forming thioamides, macroamidines, and possibly additional post-translational modifications. This review covers all knowledge through mid-2016 regarding the biosynthetic gene clusters (BGCs), natural products, functions, mechanisms, and applications of YcaO proteins and outlines likely future research directions for this protein superfamily.

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Improving on Nature: Making a Cyclic Heptapeptide Orally Bioavailable

Cited by 126 publications

References 29 publications

Beyond cyclosporine A: conformation-dependent passive membrane permeabilities of cyclic peptide natural products

Beyond cyclosporine A: conformation-dependent passive membrane permeabilities of cyclic peptide natural products

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

YcaO-Dependent Posttranslational Amide Activation: Biosynthesis, Structure, and Function

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