Design, synthesis and structural analysis of mixed α/β-peptides that adopt stable cyclic hairpin-like conformations

Knaap, Matthijs van der; Otero, José M.; Llamas-Saíz, Antonio L.; Raaij, Mark J. van; Lageveen, Lianne I.; Busscher, Henk J.; Grotenbreg, Gijsbert M.; Marel, Gijsbert A. van der; Overkleeft, Herman S.; Overhand, Mark

doi:10.1016/j.tet.2012.01.015

Cited by 14 publications

(29 citation statements)

References 79 publications

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“…[33,34] Structural studies of native GS (1) and the analogues 4-8 (see Figures 5 and 9) with 1 H and 13 C NMR spectroscopy were described in recent papers. [29,[34][35][36] The dispersion of the amide proton signals in the 1 H NMR spectrum indicated that there are no multiple conformations in solution, and the observed chemical shifts, coupling constants, and nuclear Overhauser effects demon- strated that this conformation corresponds to a stable cyclic b-hairpin configuration. The 1 H and 13 C NMR spectra for analogues 2 and 3 (see Figure 7) showed multiple signals per nucleus, which indicates that they exist in solution as multiple interchanging conformations, and although they have similar structures to gramicidin S, we cannot be certain that they adopt b-hairpin conformations.…”

Section: Introductionmentioning

confidence: 99%

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Inhibiting and Reversing Amyloid‐β Peptide (1–40) Fibril Formation with Gramicidin S and Engineered Analogues

Luo

Otero

et al. 2013

Chemistry A European J

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In Alzheimer’s disease, amyloid‐β (Aβ) peptides aggregate into extracellular fibrillar deposits. Although these deposits may not be the prime cause of the neurodegeneration that characterizes this disease, inhibition or dissolution of amyloid fibril formation by Aβ peptides is likely to affect its development. ThT fluorescence measurements and AFM images showed that the natural antibiotic gramicidin S significantly inhibited Aβ amyloid formation in vitro and could dissolve amyloids that had formed in the absence of the antibiotic. In silico docking suggested that gramicidin S, a cyclic decapeptide that adopts a β‐sheet conformation, binds to the Aβ peptide hairpin‐stacked fibril through β‐sheet interactions. This may explain why gramicidin S reduces fibril formation. Analogues of gramicidin S were also tested. An analogue with a potency that was four‐times higher than that of the natural product was identified.

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Section: Introductionmentioning

confidence: 99%

“…[25] Residues 1-17 are disordered and do not appear in the 3D model. Residues 18-42 form a hairpin-like structure with a b1-strand (18-26)-turn-b2-strand (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42) motif (Figure 1 a). At least two molecules are required to obtain a protofilament structure through the parallel packing of the b-strands.…”

Section: Introductionmentioning

confidence: 99%

Inhibiting and Reversing Amyloid‐β Peptide (1–40) Fibril Formation with Gramicidin S and Engineered Analogues

Luo

Otero

et al. 2013

Chemistry A European J

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“…-2-Nal) 2 (6). The cyclized deprotected peptide was RP-HPLC purified (linear gradient of 40→55% MeCN, 3CV) and yielded a white powder (37 mg, 41 % yield).…”

Section: Cyclo-(pro-(s)-β 3 Hleu-(r)-orn-(r)-β 2 Hval-(r)mentioning

confidence: 99%

“…3 Structure determination: Structures of 4, 6, 16 and 18 were solved by direct methods using the program SHELXD. 4 Initial phases for solving the structures of 7 and 14 were obtained with EPMR 5 using a molecular replacement procedure with the structure of 2 6 as a starting search model. All the three dimensional structures were completed and refined with no intensity cut-off using the full-matrix least-squares methods on F 2 refinement implemented in SHELXL 4 included in the WinGX package.…”

Section: Figure S1mentioning

confidence: 99%

“…Compound 2 was synthesized following a previously described procedure. 6 Dimethylsulfoxide (40 µL) was added to a freshly prepared 20 mM solution of 2 in chloroform (1 mL) and the mixture was left at room temperature for 24 hours, yielding long and narrow white needles of compound 2. Then, the suspension was diluted with a 1:1 water/methanol solution (1 mL) and one drop of the mixture was deposited over a "glass microscope slide" to take optical images on a Confocal Spectral Leica TCS-SP2 microscope.…”

Section: Figure S1mentioning

confidence: 99%

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Design, Synthesis, and Structural Analysis of Turn Modified cyclo-(αβ³αβ²α)₂ Peptide Derivatives toward Crystalline Hexagon-Shaped Cationic Nanochannel Assemblies

Otero

Knaap

Llamas-Saíz

et al. 2013

Crystal Growth & Design

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Synthesis and characterization of peptides 3-17.General methods: (S)-Fmoc-β 3 -homoleucine-OH and (R)-Fmoc-2-aminodecanoic acid were obtained from Senn Chemicals AG. Solvents and chemicals were used as received from their supplier. Solvents were stored over 4 Å molecular sieves. Solvents for column chromatography and extractions were of technical grade and distilled prior to use. THF was distilled over LiAlH 4 , CH 2 Cl 2 over CaH 2 and MeOH over NaBH 4 prior to use. All reactions were performed at room temperature under inert atmosphere. Flash chromatography was performed on Screening Devices silica gel 60 (0.04-0.063 mm). TLC analysis was conducted on DC-alufolien (Merck, Kieselgel 60, F254) with detection by UV-absorption at 254 nm or by spraying with a solution of ninhydrin (3 g/L) in EtOH/AcOH (20:1 v/v), or KMnO 4 solution (20 g in 1% aq K 2 CO 3 ), followed by charring at ~ 150 °C. 1 H and 13 C NMR spectra were recorded with a Bruker DMX-600 spectrometer (600/150 MHz) or with a Bruker AV-400liq spectrometer (400/100 MHz). Chemical shifts (δ) are given in ppm relative to TMS (0.00 ppm) or CD 3 OH (3.31 ppm) as internal standard. CD spectra were recorded at 298 K on a Jasco J-715 spectropolarimeter using 0.2 cm path length quartz cells. The CD spectra are an average of four scans, collected at 0.1 nm intervals between 190 and 250 nm with scanning speed 50 nm/min. The peptides were prepared at concentrations 0.1 mM in MeOH. Ellipticity is reported as mean residue ellipticity [θ], with approximate errors of ±10% at 220 nm. High resolution mass spectra were recorded by direct injection (2 μL of a 2 μM solution in water/acetonitrile; 50:50 v/v and 0.1% formic acid) on a mass spectrometer (Thermo Finnigan LTQ Orbitrap) equipped with an electro spray ion source in positive mode (source voltage 3.5 kV, sheath gas flow 10, capillary temperature 250˚C) with resolution R = 60000 at m/z 400 (mass range m/z = 150-2000) and dioctylphthalate (m/z = 391.28428) as a "lock mass". The high resolution mass spectrometer was calibrated prior to measurements with a calibration mixture (Thermo Finnigan). LC/MS analyses were performed on a LCQ Adventage Max (Thermo Finnigan) equipped with a Gemini C18 column (Phenomenex). The applied buffers were A: H 2 O, B: MeCN and C: 1.0% aq. TFA. HPLC purifications were performed with a Gilson GX-281 automated HPLC system, equipped with a preparative Gemini C18 column (150 × 21.20 mm, 5μ). The applied buffers were: A: 0.2% aq. TFA, B: MeCN. Loading of the HMPB-MBHA-resin:The HMPB-MBHA-resin (theoretical loading = 1.2 mmol/g, 2 mmol, 1.67 g) was suspended in 1,2-dichloroethane (10 mL) and concentrated thrice. Then a solution of the first amino acid (5 eq, 10 mmol), DIC (5 eq, 10 mmol, 1.54 mL) and DMAP (0.01 eq, 20 μmol, 3 mg) in dry DCM/DMF (50 mL, 10:1 v/v) was added. The mixture was shaken for 3 hours and then drained, washed subsequently with DCM, NMP, DCM and Et 2 O. The resin was dried before determination of the loading. The loading procedure was repeated when the loading of the resin wa...

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Synthesis and Biological Evaluation of Gramicidin S‐Inspired Cyclic Mixed α/β‐Peptides

Knaap

Basalan

Mei

et al. 2012

Chemistry & Biodiversity

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Via a Mannich reaction involving a dibenzyliminium species and the titanium enolates of Evans' chiral acylated oxazolidinones the β(2)-amino acids (R)- and (S)-Fmoc-β(2)homovaline and (R)-Fmoc-β(2)homoleucine are synthesized. These building blocks were used, in combination with commercially available α- and β(3)-amino acids, for the synthesis of the cyclo-(αβ(3)αβ(2)α)(2) peptide 2 and the cyclo-(αβ(2)αβ(3)α)(2) peptides 3-5. The peptides 2-5 were screened for their ability to inhibit a small panel of Gram-negative and Gram-positive bacterial strains.

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Design, synthesis and structural analysis of mixed α/β-peptides that adopt stable cyclic hairpin-like conformations

Cited by 14 publications

References 79 publications

Inhibiting and Reversing Amyloid‐β Peptide (1–40) Fibril Formation with Gramicidin S and Engineered Analogues

Inhibiting and Reversing Amyloid‐β Peptide (1–40) Fibril Formation with Gramicidin S and Engineered Analogues

Design, Synthesis, and Structural Analysis of Turn Modified cyclo-(αβ³αβ²α)₂ Peptide Derivatives toward Crystalline Hexagon-Shaped Cationic Nanochannel Assemblies

Synthesis and Biological Evaluation of Gramicidin S‐Inspired Cyclic Mixed α/β‐Peptides

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Design, synthesis and structural analysis of mixed α/β-peptides that adopt stable cyclic hairpin-like conformations

Cited by 14 publications

References 79 publications

Inhibiting and Reversing Amyloid‐β Peptide (1–40) Fibril Formation with Gramicidin S and Engineered Analogues

Inhibiting and Reversing Amyloid‐β Peptide (1–40) Fibril Formation with Gramicidin S and Engineered Analogues

Design, Synthesis, and Structural Analysis of Turn Modified cyclo-(αβ3αβ2α)2 Peptide Derivatives toward Crystalline Hexagon-Shaped Cationic Nanochannel Assemblies

Synthesis and Biological Evaluation of Gramicidin S‐Inspired Cyclic Mixed α/β‐Peptides

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Design, Synthesis, and Structural Analysis of Turn Modified cyclo-(αβ³αβ²α)₂ Peptide Derivatives toward Crystalline Hexagon-Shaped Cationic Nanochannel Assemblies