Cyclic Peptides as Molecular Adapters for a Pore-Forming Protein

Sánchez‐Quesada, Jorge; Ghadiri, Mojtaba; Bayley, Hagan; Braha, Orit

doi:10.1021/ja002436k

Cited by 136 publications

(104 citation statements)

References 54 publications

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“…The observed effects of CP 7 provide further evidence of the previously demonstrated importance of alternating L-and D-amino acids in cyclopeptides. [28,29] The above killing curve results are consistent with the rapid killing rates associated with the detergent-like mode of action on the bacterial membrane. The microbial membrane disrupting effect of these cationic amphipathic cyclopeptides could provide general accessibility into the bacteria.…”

Section: Time Course Assaysupporting

confidence: 76%

In Vitro Synergy Between Some Cationic Amphipathic Cyclooctapeptides and Antibiotics

et al. 2015

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The antimicrobial activities of some cationic amphipathic cyclooctapeptides in combination with select antibiotics are investigated. Accordingly, cyclooctapeptides (CPs 1-11) derived from the sequence cyclo[Leu-D-Leu-Leu-D-Leu-Lys-DLys-Lys-D-Lys] were tested against Escherichia coli and Staphylococcus aureus. Synergistic effects were evaluated in combination with tetracycline, chloramphenicol, oflaxacin, rifampicin, colistin, clindamycin, and vancomycin by the checkerboard titration assay. The results show that these cyclooctapeptides are fast acting bactericidals and are comparable to the related a-helical peptides in their activities. Significantly, some of these cyclooctapeptides exert selective synergistic effects in combination with the bacteriostatic tetracycline against S. aureus; a greater than 4-fold decrease in the minimum inhibition concentration was observed. Their synergism with the other evaluated antibiotics was generally partial or additive. Cationic amphipathic cyclooctapeptides in combination with some antibiotics could offer a possible solution to the increasing antimicrobial resistance predicament.

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Section: Time Course Assaysupporting

confidence: 76%

In Vitro Synergy Between Some Cationic Amphipathic Cyclooctapeptides and Antibiotics

et al. 2015

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“…[4][5][6][7][8][9][10] It has been demonstrated using experimental and theoretical studies that a CPNT embedded in a lipid bilayer can act as an active transporter for various molecules. [4][5][6][7][8][11][12][13] Granja et al showed that 3 is characterized as the alternating Cα and mid-Cα regions. The plane formed by the Cα atoms in a CP is called the Cα plane.…”

Section: Introductionmentioning

confidence: 99%

Theoretical studies on the transport mechanism of 5-fluorouracil through cyclic peptide based nanotubes

Vijayaraj

Damme

Bultinck

et al. 2013

Phys. Chem. Chem. Phys.

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Cyclic peptide nanotubes (CPNTs) formed by the self-assembly of cyclic peptides (CPs) with an even number of alternate L/D amino acids are typically used in the field of the transport of ions and drug molecules across the lipid bilayer. This study investigates the transport mechanism of the antitumor drug molecule, 5-Fluorouracil (5FU), through the CPNT using classical and steered molecular dynamics simulations combined with umbrella sampling.During the transport of 5FU through the CPNT, 5FU is partially desolvated because the lumen of the CPNT is too small to allow for water molecules solvating it. 5FU forms Hbonding interactions with the backbones of CPNT and at the same time, also forms hydrophobic contacts with the backbone Cα and C atoms of CPNT. The cooperative breaking of the H-bond and hydrophobic interactions between CPNT and 5FU increases the pulling force to transport the 5FU from the mid-Cα region to the Cα one. The calculated free energies of binding reveal that the energy barriers for the transport of 5FU are ~ -6.0 and ~ -2.0 kcal/mol in the mid-Cα and Cα plane regions, respectively.

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“…The result is similar to the effect of high potentials on charged cyclic peptides. [9] The product of the electrical distance (d) and the charge associated with CB6 (z) was derived from the voltage dependence of K …”

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confidence: 99%

Carriers versus Adapters in Stochastic Sensing

Braha

Webb

et al. 2005

ChemPhysChem

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Sensors based on analyte-dependent changes in the conduction of transmembrane protein pores are an interesting prospect. Stochastic sensing, that is, the detection of individual analyte molecules by single pores, has several potential advantages and a variety of sensor elements based on engineered forms of staphylococcal a-hemolysin (aHL) has been tested. [1] In one manifestation of this approach, organic molecules have been detected by using molecular adapters, such as cyclodextrins, which continue to engage in dynamic host-guest interactions after they have become lodged within the lumen of the aHL pore.[2] Here, we show that small organic molecules can also be detected by a scheme in which a host, cucurbit[6]uril (CB6), [3] acts as a carrier rather than an adapter. In this case, the rate of exchange of the guest between the host·guest complex and bulk solvent is slower [4] than the rate of exchange of the host between the solvent and its binding site within the aHL pore. Besides providing a useful means for sensing organic molecules, the carrier system allows the determination of dissociation constants and, independently, association and dissociation rate constants for CB6·guest pairs.CB6 ( Figure 1) contains a hydrophobic cavity, % 5.5 in diameter, which can host small neutral organic molecules.[3] Six carbonyl groups are located at each of the two 4--diameter entrances to the cavity. CB6 is sparingly soluble in water, but its solubility increases in the presence of alkali-metal salts because the carbonyl groups coordinate to the metal cations to form positively charged complexes. [5,6] An X-ray structure of CB6, which was crystallized from an aqueous solution containing Na + ions, shows two sodium ions and their coordinated water molecules at each entrance. [5,6] By contrast, when CB6 is crystallized in the presence of Cs + , only one cesium ion is associated with each entrance.[6] The dimensions of CB6 (maximum external diameter % 14.4 ) suggested that it might become lodged in the lumen of the aHL pore (Figure 1), similar to b-cyclodextrin (diameter % 15.5 ), and mediate the detection of analytes through host-guest interactions.The interaction of CB6 with the aHL pore was first examined in the absence of analyte by monitoring the current through a single pore in a planar bilayer apparatus, as described previously. [7] At + 100 mV in 1.0 m CsCl/10 mm K phosphate buffer (pH 7.4), the current measured through a fully open aHL pore (level L1) was 93.3 AE 1.2 pA (n = 7), and the current with CB6 bound from the trans side (level L2, aHL·CB6) was 41.7 AE 1.5 pA (n = 7) (Figure 2). Binding events were not detected when CB6 was applied to the cis side of the bilayer. The mean interevent intervals (t on ) and the mean durations of the binding events (t off ) were determined from dwell-time histograms.[8]The value of 1/t on increased linearly with [CB6], where [CB6] is the concentration of the cucurbituril, which suggests a simple bimolecular interaction (Scheme 1).[8] The rate constants for association and dissociat...

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Cyclic Peptides as Molecular Adapters for a Pore-Forming Protein

Cited by 136 publications

References 54 publications

In Vitro Synergy Between Some Cationic Amphipathic Cyclooctapeptides and Antibiotics

In Vitro Synergy Between Some Cationic Amphipathic Cyclooctapeptides and Antibiotics

Theoretical studies on the transport mechanism of 5-fluorouracil through cyclic peptide based nanotubes

Carriers versus Adapters in Stochastic Sensing

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