Browse
Submit Data
Databases
API
Help

Dataset Information

20 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Giant macrolactams based on ?-sheet peptides.

ABSTRACT: This paper reports the use of natural amino acids, the tripeptide ?-strand mimic Hao, and the ?-turn mimic ?-linked ornithine to generate water-soluble 54-, 78-, and 102-membered-ring macrolactams. These giant macrocycles were efficiently prepared by synthesis of the corresponding protected linear peptides, followed by solution-phase cyclization and deprotection. The protected linear peptide precursors were synthesized on 2-chlorotrityl chloride resin by conventional Fmoc-based solid-phase peptide synthesis. Macrocyclization was typically performed using HCTU and N,N-diisopropylethylamine in DMF at ca. 0.5 mM concentration. The macrocycles were isolated in 13-45% overall yield after HPLC purification and lyophilization. 1D, 2D TOCSY, and 2D ROESY (1)H NMR studies of the 54- and 78-membered-ring macrolactams establish that these compounds fold to form ?-sheet structures in aqueous solutions.

SUBMITTER: Cheng PN

PROVIDER: S-EPMC3088102 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Giant macrolactams based on β-sheet peptides.

Cheng Pin-Nan PN Nowick James S JS

The Journal of organic chemistry 20110415 9

This paper reports the use of natural amino acids, the tripeptide β-strand mimic Hao, and the β-turn mimic δ-linked ornithine to generate water-soluble 54-, 78-, and 102-membered-ring macrolactams. These giant macrocycles were efficiently prepared by synthesis of the corresponding protected linear peptides, followed by solution-phase cyclization and deprotection. The protected linear peptide precursors were synthesized on 2-chlorotrityl chloride resin by conventional Fmoc-based solid-phase pepti ...[more]

PMID: 21452877

Similar Datasets

De novo design of peptides that coassemble into β sheet-based nanofibrils.

Project description:[Figure: see text].

| S-EPMC8442925 | biostudies-literature

Engineered nanostructured ?-sheet peptides protect membrane proteins.

Project description:We designed ?-strand peptides that stabilize integral membrane proteins (IMPs). ?-strand peptides self-assemble in solution as filaments and become restructured upon association with IMPs; resulting IMP-?-strand peptide complexes resisted aggregation when diluted in detergent-free buffer and were visible as stable, single particles with low detergent background in electron micrographs. ?-strand peptides enabled clear visualization of flexible conformations in the highly dynamic ATP-binding cassette (ABC) transporter MsbA.

| S-EPMC3753066 | biostudies-literature

Macrocyclic beta-sheet peptides that mimic protein quaternary structure through intermolecular beta-sheet interactions.

Project description:This paper reports the design, synthesis, and characterization of a family of cyclic peptides that mimic protein quaternary structure through beta-sheet interactions. These peptides are 54-membered-ring macrocycles comprising an extended heptapeptide beta-strand, two Hao beta-strand mimics [JACS 2000, 122, 7654] joined by one additional alpha-amino acid, and two delta-linked ornithine beta-turn mimics [JACS 2003, 125, 876]. Peptide 3a, as the representative of these cyclic peptides, contains a heptapeptide sequence (TSFTYTS) adapted from the dimerization interface of protein NuG2 [PDB ID: 1mio]. 1H NMR studies of aqueous solutions of peptide 3a show a partially folded monomer in slow exchange with a strongly folded oligomer. NOE studies clearly show that the peptide self-associates through edge-to-edge beta-sheet dimerization. Pulsed-field gradient (PFG) NMR diffusion coefficient measurements and analytical ultracentrifugation (AUC) studies establish that the oligomer is a tetramer. Collectively, these experiments suggest a model in which cyclic peptide 3a oligomerizes to form a dimer of beta-sheet dimers. In this tetrameric beta-sheet sandwich, the macrocyclic peptide 3a is folded to form a beta-sheet, the beta-sheet is dimerized through edge-to-edge interactions, and this dimer is further dimerized through hydrophobic face-to-face interactions involving the Phe and Tyr groups. Further studies of peptides 3b-3n, which are homologues of peptide 3a with 1-6 variations in the heptapeptide sequence, elucidate the importance of the heptapeptide sequence in the folding and oligomerization of this family of cyclic peptides. Studies of peptides 3b-3g show that aromatic residues across from Hao improve folding of the peptide, while studies of peptides 3h-3n indicate that hydrophobic residues at positions R3 and R5 of the heptapeptide sequence are important in oligomerization.

| S-EPMC2596933 | biostudies-literature

Coassembly of Peptides Derived from ?-Sheet Regions of ?-Amyloid.

Project description:In this paper, we investigate the coassembly of peptides derived from the central and C-terminal regions of the ?-amyloid peptide (A?). In the preceding paper, J. Am. Chem. Soc. 2016, DOI: 10.1021/jacs.6b06000 , we established that peptides containing residues 17-23 (LVFFAED) from the central region of A? and residues 30-36 (AIIGLMV) from the C-terminal region of A? assemble to form homotetramers consisting of two hydrogen-bonded dimers. Here, we mix these tetramer-forming peptides and determine how they coassemble. Incorporation of a single 15N isotopic label into each peptide provides a spectroscopic probe with which to elucidate the coassembly of the peptides by 1H,15N HSQC. Job's method of continuous variation and nonlinear least-squares fitting reveal that the peptides form a mixture of heterotetramers in 3:1, 2:2, and 1:3 stoichiometries, in addition to the homotetramers. These studies also establish the relative stability of each tetramer and show that the 2:2 heterotetramer predominates. 15N-Edited NOESY shows the 2:2 heterotetramer comprises two different homodimers, rather than two heterodimers. The peptides within the heterotetramer segregate in forming the homodimer subunits, but the two homodimers coassemble in forming the heterotetramer. These studies show that the central and C-terminal regions of A? can preferentially segregate within ?-sheets and that the resulting segregated ?-sheets can further coassemble.

| S-EPMC5089069 | biostudies-literature

Assembly of Peptides Derived from ?-Sheet Regions of ?-Amyloid.

Project description:In Alzheimer's disease, aggregation of the ?-amyloid peptide (A?) results in the formation of oligomers and fibrils that are associated with neurodegeneration. Aggregation of A? occurs through interactions between different regions of the peptide. This paper and the accompanying paper constitute a two-part investigation of two key regions of A?: the central region and the C-terminal region. These two regions promote aggregation and adopt ?-sheet structure in the fibrils, and may also do so in the oligomers. In this paper, we study the assembly of macrocyclic ?-sheet peptides that contain residues 17-23 (LVFFAED) from the central region and residues 30-36 (AIIGLMV) from the C-terminal region. These peptides assemble to form tetramers. Each tetramer consists of two hydrogen-bonded dimers that pack through hydrophobic interactions in a sandwich-like fashion. Incorporation of a single 15N isotopic label into each peptide provides a spectroscopic probe with which to elucidate the ?-sheet assembly and interaction: 1H,15N HSQC studies facilitate the identification of the monomers and tetramers; 15N-edited NOESY studies corroborate the pairing of the dimers within the tetramers. In the following paper, J. Am. Chem. Soc. 2016, DOI: 10.1021/jacs.6b06001 , we will extend these studies to elucidate the coassembly of the peptides to form heterotetramers.

| S-EPMC5089065 | biostudies-literature

Designed multi-stranded heme binding ?-sheet peptides in membrane.

Project description:Designed peptides demonstrating well-defined structures and functioning in membrane environment are of significant interest in developing novel proteins for membrane active biological processes including enzymes, electron transfer, ion channels and energy conversion. Heme proteins' ability to carry out multiple functions in nature has inspired the design of several helical heme binding peptides and proteins soluble in water and also recently in membrane. Naturally occurring ?-sheet proteins are both water and membrane soluble, and are known to bind heme, however, designed heme binding ?-sheet proteins are yet to be reported, plausibly because of the complex folding and difficulty in introducing heme binding sites in the ?-sheet structures. Here, we describe the design, NMR structures and biochemical functional characterization of four stranded and six stranded membrane soluble ?-sheet peptides that bind heme and di-heme, respectively. The designed peptides contain either DP-G or DP-DA residues for the nucleation of ?-turns intended to stabilize multi-stranded ?-sheet topologies and ligate heme with bis-His coordination between adjacent antiparallel ?-strands. Furthermore, we have optimized a high affinity heme binding pocket, Kd ? nM range, in the adjacent ?-strands by utilizing a series of four stranded ?-sheet peptides employing ?- and ?-amino acids. We find that there is a progressive increase in cofactor binding affinity in the designed peptides with the alkyl chain length of ?-amino acids. Notably, the six stranded ?-sheet peptide binds two molecules of heme in a cooperative fashion. The designed peptides perform peroxidase activity with varying ability and efficiently carried out electron transfer with membrane associated protein cytochrome c. The current study demonstrates the designing of functional ?-sheet proteins in a membrane environment and expands the repertoire of heme protein design.

| S-EPMC5477022 | biostudies-literature

Designed ?-sheet peptides inhibit amyloid formation by targeting toxic oligomers.

Project description:Previous studies suggest that the toxic soluble-oligomeric form of different amyloid proteins share a common backbone conformation, but the amorphous nature of this oligomer prevents its structural characterization by experiment. Based on molecular dynamics simulations we proposed that toxic intermediates of different amyloid proteins adopt a common, nonstandard secondary structure, called ?-sheet. Here we report the experimental characterization of peptides designed to be complementary to the ?-sheet conformation observed in the simulations. We demonstrate inhibition of aggregation in two different amyloid systems, ?-amyloid peptide (A?) and transthyretin, by these designed ?-sheet peptides. When immobilized the ?-sheet designs preferentially bind species from solutions enriched in the toxic conformer compared with non-aggregated, nontoxic species or mature fibrils. The designs display characteristic spectroscopic signatures distinguishing them from conventional secondary structures, supporting ?-sheet as a structure involved in the toxic oligomer stage of amyloid formation and paving the way for novel therapeutics and diagnostics.DOI: http://dx.doi.org/10.7554/eLife.01681.001.

| S-EPMC4091096 | biostudies-literature

Coassembly of enantiomeric amphipathic peptides into amyloid-inspired rippled ?-sheet fibrils.

Project description:Amphipathic peptides composed of alternating hydrophobic and hydrophilic amino acids self-assemble into amyloid-inspired, ?-sheet nanoribbon fibrils. Herein, we report a new fibril type that is formed from equimolar mixtures of enantiomeric amphipathic peptides (L- and D-(FKFE)(2)). Spectroscopic analysis indicates that these peptides do not self-sort and assemble into enantiomeric fibrils composed of all-l and all-d peptides, but rather coassemble into fibrils that contain alternating L- and D-peptides in a "rippled ?-sheet" orientation. Isothermal titration calorimetry indicates an enthalpic advantage for rippled ?-sheet coassembly compared to self-sorted ?-sheet assembly of enantiomeric peptides.

| S-EPMC7316157 | biostudies-literature

Designed ?-sheet peptides suppress amyloid formation in <i>Staphylococcus aureus</i> biofilms.

Project description:Nosocomial infections affect hundreds of millions of patients worldwide each year, and ~60% of these infections are associated with biofilm formation on an implanted medical device. Biofilms are dense communities of microorganisms in which cells associate with surfaces and each other using a self-produced extracellular matrix composed of proteins, polysaccharides, and genetic material. Proteins in the extracellular matrix take on a variety of forms, but here we focus on functional amyloid structures. Amyloids have long been associated with protein misfolding and neurodegenerative diseases, but recent research has demonstrated that numerous bacterial species utilize the amyloid fold to fortify the biofilm matrix and resist disassembly. Consequently, these functional amyloids, in particular the soluble oligomeric intermediates formed during amyloidogenesis, represent targets to destabilize the extracellular matrix and interrupt biofilm formation. Our previous studies suggested that these amyloidogenic intermediates adopt a non-standard structure, termed "?-sheet", as they aggregate into soluble oligomeric species. This led to the design of complementary ?-sheet peptides as anti-?-sheet inhibitors; these designs inhibit amyloidogenesis in three unrelated mammalian disease-associated systems through preferential binding of soluble oligomers. Here we show that these anti-?-sheet peptides inhibit amyloid formation in Staphylococcus aureus biofilms. Furthermore, they inhibit aggregation of pure, synthetic phenol soluble modulin ?1, a major component of Staphylococcus aureus functional amyloids. As it aggregates phenol soluble modulin ?1 adopts ?-helix then ?-sheet and finally forms ?-sheet fibrils. The binding of the designed peptide inhibitors coincides with the formation of ?-sheet.

| S-EPMC5495782 | biostudies-literature

Topomimetics of amphipathic beta-sheet and helix-forming bactericidal peptides neutralize lipopolysaccharide endotoxins.

Project description:Release of lipopolysaccharide (LPS) endotoxin from Gram negative bacterial membranes triggers macrophages to produce large quantities of cytokines that can lead to septic shock and eventual death. Agents that bind to and neutralize LPS may provide a means to clinically prevent septic shock upon bacterial infection. Previously, we reported the design of antibacterial helix peptide SC4 and beta-sheet-forming betapep peptides that neutralize LPS in vitro. We hypothesized that the ability of these and other such peptides to neutralize LPS rested in the common denominator of positively charged amphipathic structure. Here, we describe the design and synthesis of nonpeptide, calixarene-based helix/sheet topomimetics that mimic the folded conformations of these peptides in their molecular dimensions, amphipathic surface topology, and compositional properties. From a small library of topomimetics, we identified several compounds that neutralize LPS in the 10-8 M range, making them as effective as bactericidal/permeability increasing protein and polymyxin B. In an endotoxemia mouse model, three of the most in vitro effective topomimetics are shown to be at least partially protective against challenges of LPS from different bacterial species. NMR studies provide mechanistic insight by suggesting the site of molecular interaction between topomimetics and the lipid A component of LPS, with binding being mediated by electrostatic and hydrophobic interactions. This research contributes to the development of pharmaceutical agents against endotoxemia and septic shock.

| S-EPMC4242098 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data