Helical peptaibol mimics are better ionophores when racemic than when enantiopure

Pike, Sarah J.; Jones, Jennifer E.; Raftery, James; Clayden, Jonathan; Webb, Simon J.

doi:10.1039/c5ob01652e

Cited by 14 publications

(22 citation statements)

References 46 publications

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“…Peptides 1 to 9 were synthesized according to previously published procedures . All samples were re‐purified by high‐performance liquid chromatography (HPLC) on an Agilent (Santa Clara, California, United States) 1100 series HPLC equipped with a semi‐preparative C‐18 column (Agilent Eclipse XDB‐C18, 5 μm, 9.4 mm×250 mm).…”

Section: Methodssupporting

confidence: 83%

“…Like the naturally occurring peptaibols, foldamers 1 to 9 have both N‐ and C‐ termini functionalized. These caps can modulate the stability of the 3 10 ‐helix, for example, a t Bu ester induces formation of a destabilizing Schellman‐like motif at the C‐terminus of the peptides, whilst an N‐terminal Cbz (PhCH 2 OC(O)) adds an extra hydrogen bond that can stabilize the 3 10 ‐helix . Nonetheless, Aib foldamers with four residues or more form 3 10 ‐helical structures even in the presence of destabilizing capping groups.…”

Section: Resultsmentioning

confidence: 99%

“…As well as providing a chiral influence, appending these residues to the Aib tetramer body can also stabilize the helix. The solid state structure of ( rac )‐ 8 shows that adding a single Cbz‐protected residue to the N‐terminus of an Aib tetramer adds two intramolecular hydrogen bonds, to give three hydrogen bonds that stabilize the 3 10 ‐helix …”

Section: Resultsmentioning

confidence: 99%

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Optically Active Vibrational Spectroscopy of α‐Aminoisobutyric Acid Foldamers in Organic Solvents and Phospholipid Bilayers

Lizio

Andrushchenko

Pike

et al. 2018

Chemistry A European J

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Helical α-aminoisobutyric acid (Aib) foldamers show great potential as devices for the communication of conformational information across phospholipid bilayers, but determining their conformation in bilayers remains a challenge. In the present study, Raman, Raman optical activity (ROA), infrared (IR) and vibrational circular dichroism (VCD) spectroscopies have been used to analyze the conformational preferences of Aib foldamers in solution and when interacting with bilayers. A 3 -helix marker band at 1665-1668 cm in Raman spectra was used to show that net helical content increased strongly with oligomer length. ROA and VCD spectra of chiral Aib foldamers provided the chiroptical signature for both left- and right-handed 3 -helices in organic solvents, with VCD establishing that foldamer screw-sense was preserved when the foldamers became embedded within bilayers. However, the population distribution between different secondary structures was perturbed by the chiral phospholipid. These studies indicate that ROA and VCD spectroscopies are valuable tools for the study of biomimetic structures, such as artificial signal transduction molecules, in phospholipid bilayers.

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Section: Methodssupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Optically Active Vibrational Spectroscopy of α‐Aminoisobutyric Acid Foldamers in Organic Solvents and Phospholipid Bilayers

Lizio

Andrushchenko

Pike

et al. 2018

Chemistry A European J

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“…Aib foldamers that were too short to span the membrane were much less active. They may act through an “amyloid-like” mechanism that has been suggested for other short Aib foldamers, 57 where at high concentrations the foldamers assemble in or around the membrane surface, porating and weakening the bilayer. The longer foldamers were remarkably effective ionophores.…”

Section: Discussionmentioning

confidence: 99%

Length-Dependent Formation of Transmembrane Pores by 3₁₀-Helical α-Aminoisobutyric Acid Foldamers

et al. 2016

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The synthetic biology toolbox lacks extendable and conformationally controllable yet easy-to-synthesize building blocks that are long enough to span membranes. To meet this need, an iterative synthesis of α-aminoisobutyric acid (Aib) oligomers was used to create a library of homologous rigid-rod 310-helical foldamers, which have incrementally increasing lengths and functionalizable N- and C-termini. This library was used to probe the inter-relationship of foldamer length, self-association strength, and ionophoric ability, which is poorly understood. Although foldamer self-association in nonpolar chloroform increased with length, with a ∼14-fold increase in dimerization constant from Aib6 to Aib11, ionophoric activity in bilayers showed a stronger length dependence, with the observed rate constant for Aib11 ∼70-fold greater than that of Aib6. The strongest ionophoric activity was observed for foldamers with >10 Aib residues, which have end-to-end distances greater than the hydrophobic width of the bilayers used (∼2.8 nm); X-ray crystallography showed that Aib11 is 2.93 nm long. These studies suggest that being long enough to span the membrane is more important for good ionophoric activity than strong self-association in the bilayer. Planar bilayer conductance measurements showed that Aib11 and Aib13, but not Aib7, could form pores. This pore-forming behavior is strong evidence that Aibm (m ≥ 10) building blocks can span bilayers.

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“…We have observed membrane activity for Aib foldamers containing as few as 5 residues, but studies on the N 3 Aib n C(O)OCH 2 CH 2 SiMe 3 compound family ( n =4 to 13) showed a strong increase in activity when n ≥9 (Figure c) . Planar bilayer conductance (PBC) studies showed clear channel‐like behaviour for n =11 and 13, but not for n =7 and 8 .…”

Section: Resultsmentioning

confidence: 99%

The Role of Terminal Functionality in the Membrane and Antibacterial Activity of Peptaibol‐Mimetic Aib Foldamers

Adam

Peters

Lizio

et al. 2018

Chemistry A European J

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Peptaibols are peptide antibiotics that typically feature an N-terminal acetyl cap, a C-terminal aminoalcohol, and a high proportion of α-aminoisobutyric acid (Aib) residues. To establish how each feature might affect the membrane-activity of peptaibols, biomimetic Aib foldamers with different lengths and terminal groups were synthesised. Vesicle assays showed that long foldamers (eleven Aib residues) with hydrophobic termini had the highest ionophoric activity. C-terminal acids or primary amides inhibited activity, while replacement of an N-terminal acetyl with an azide group made little difference. Crystallography showed that N Aib CH OTIPS folded into a 3 helix 2.91 nm long, which is close to the bilayer hydrophobic width. Planar bilayer conductance assays showed discrete ion channels only for N-acetylated foldamers. However long foldamers with hydrophobic termini had the highest antibacterial activity, indicating that ionophoric activity in vesicles was a better indicator of antibacterial activity than the observation of discrete ion channels.

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Helical peptaibol mimics are better ionophores when racemic than when enantiopure

Cited by 14 publications

References 46 publications

Optically Active Vibrational Spectroscopy of α‐Aminoisobutyric Acid Foldamers in Organic Solvents and Phospholipid Bilayers

Optically Active Vibrational Spectroscopy of α‐Aminoisobutyric Acid Foldamers in Organic Solvents and Phospholipid Bilayers

Length-Dependent Formation of Transmembrane Pores by 3₁₀-Helical α-Aminoisobutyric Acid Foldamers

The Role of Terminal Functionality in the Membrane and Antibacterial Activity of Peptaibol‐Mimetic Aib Foldamers

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Helical peptaibol mimics are better ionophores when racemic than when enantiopure

Cited by 14 publications

References 46 publications

Optically Active Vibrational Spectroscopy of α‐Aminoisobutyric Acid Foldamers in Organic Solvents and Phospholipid Bilayers

Optically Active Vibrational Spectroscopy of α‐Aminoisobutyric Acid Foldamers in Organic Solvents and Phospholipid Bilayers

Length-Dependent Formation of Transmembrane Pores by 310-Helical α-Aminoisobutyric Acid Foldamers

The Role of Terminal Functionality in the Membrane and Antibacterial Activity of Peptaibol‐Mimetic Aib Foldamers

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Length-Dependent Formation of Transmembrane Pores by 3₁₀-Helical α-Aminoisobutyric Acid Foldamers