Browse
Submit Data
Databases
API
Help

Dataset Information

27 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

?-Helix mimicry with ?/?-peptides.

ABSTRACT: We describe a general strategy for creating peptidic oligomers that have unnatural backbones but nevertheless adopt a conformation very similar to the ?-helix. These oligomers contain both ?- and ?-amino acid residues (?/?-peptides). If the ? content reaches 25-30% of the residue total, and the ? residues are evenly distributed along the backbone, then substantial resistance to proteolytic degradation is often observed. These ?/?-peptides can mimic the informational properties of ?-helices involved in protein-protein recognition events, as documented in numerous crystal structures. Thus, these unnatural oligomers can be a source of antagonists of undesirable protein-protein interactions that are mediated by natural ?-helices, or agonists of receptors for which the natural polypeptide ligands are ?-helical. Successes include mimicry of BH3 domains found in proapoptotic proteins, which leads to ligands for antiapoptotic Bcl-2 family proteins, and mimicry of the gp41 CHR domain, which leads to inhibition of HIV infection in cell-based assays.

SUBMITTER: Johnson LM

PROVIDER: S-EPMC3928965 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Extending foldamer design beyond α-helix mimicry: α/β-peptide inhibitors of vascular endothelial growth factor signaling.

Project description:Diverse strategies have been explored to mimic the surface displayed by an α-helical segment of a protein, with the goal of creating inhibitors of helix-mediated protein-protein interactions. Many recognition surfaces on proteins, however, are topologically more complex and less regular than a single α-helix. We describe efforts to develop peptidic foldamers that bind to the irregular receptor-recognition surface of vascular endothelial growth factor (VEGF). Our approach begins with a 19-residue α-peptide previously reported by Fairbrother et al. (Biochemistry 1998, 37, 17754) to bind to this surface on VEGF. Systematic evaluation of α→β replacements throughout this 19-mer sequence enabled us to identify homologues that contain up to ~30% β residues, retain significant affinity for VEGF, and display substantial resistance to proteolysis. These α/β-peptides can block VEGF-stimulated proliferation of human umbilical vein endothelial cells.

| S-EPMC3551614 | biostudies-literature

Enhancement of α-helix mimicry by an α/β-peptide foldamer via incorporation of a dense ionic side-chain array.

Project description:We report a new method for preorganization of α/β-peptide helices, based on the use of a dense array of acidic and basic side chains. Previously we have used cyclically constrained β residues to promote α/β-peptide helicity; here we show that an engineered ion pair array can be comparably effective, as indicated by mimicry of the CHR domain of HIV protein gp41. The new design is effective in biochemical and cell-based infectivity assays; however, the resulting α/β-peptide is susceptible to proteolysis. This susceptibility was addressed via introduction of a few cyclic β residues near the cleavage site, to produce the most stable, effective α/β-peptide gp41 CHR analogue identified. Crystal structures of an α- and α/β-peptide (each involved in a gp41-mimetic helix bundle) that contain the dense acid/base residue array manifest disorder in the ionic side chains, but there is little side-chain disorder in analogous α- and α/β-peptide structures with a sparser ionic side-chain array. These observations suggest that dense arrays of complementary acidic and basic residues can provide conformational stabilization via Coulombic attractions that do not require entropically costly ordering of side chains.

| S-EPMC3377471 | biostudies-literature

Iterative Nonproteinogenic Residue Incorporation Yields α/β-Peptides with a Helix-Loop-Helix Tertiary Structure and High Affinity for VEGF.

Project description:Inhibition of specific protein-protein interactions is attractive for a range of therapeutic applications, but the large and irregularly shaped contact surfaces involved in many such interactions make it challenging to design synthetic antagonists. Here, we describe the development of backbone-modified peptides containing both α- and β-amino acid residues (α/β-peptides) that target the receptor-binding surface of vascular endothelial growth factor (VEGF). Our approach is based on the Z-domain, which adopts a three-helix bundle tertiary structure. We show how a two-helix "mini-Z-domain" can be modified to contain β and other nonproteinogenic residues while retaining the target-binding epitope by using iterative unnatural residue incorporation. The resulting α/β-peptides are less susceptible to proteolysis than is their parent α-peptide, and some of these α/β-peptides match the full-length Z-domain in terms of affinity for receptor-recognition surfaces on the VEGF homodimer.

| S-EPMC5384266 | biostudies-literature

Aromatic-Aromatic Interactions Enable α-Helix to β-Sheet Transition of Peptides to Form Supramolecular Hydrogels.

Project description:Isolated short peptides usually are unable to maintain their original secondary structures due to the lack of the restriction from proteins. Here we show that two complementary pentapeptides from a β-sheet motif of a protein, being connected to an aromatic motif (i.e., pyrene) at their C-terminal, self-assemble to form β-sheet like structures upon mixing. Besides enabling the self-assembly to result in supramolecular hydrogels upon mixing, aromatic-aromatic interactions promote the pentapeptides transform from α-helix to β-sheet conformation. As the first example of using aromatic-aromatic interactions to mimic the conformational restriction in a protein, this work illustrates a bioinspired way to generate peptide nanofibers with predefined secondary structures of the peptides by a rational design using protein structures as the blueprint.

| S-EPMC5477776 | biostudies-literature

Alpha-helix targeting reduces amyloid-beta peptide toxicity.

Project description:The amyloid-beta peptide (Abeta) can generate cytotoxic oligomers, and their accumulation is thought to underlie the neuropathologic changes found in Alzheimer's disease. Known inhibitors of Abeta polymerization bind to undefined structures and can work as nonspecific aggregators, and inhibitors that target conformations that also occur in larger Abeta assemblies may even increase oligomer-derived toxicity. Here we report on an alternative approach whereby ligands are designed to bind and stabilize the 13-26 region of Abeta in an alpha-helical conformation, inspired by the postulated Abeta native structure. This is achieved with 2 different classes of compounds that also reduce Abeta toxicity to cells in culture and to hippocampal slice preparations, and that do not show any nonspecific aggregatory properties. In addition, when these inhibitors are administered to Drosophila melanogaster expressing human Abeta(1-42) in the central nervous system, a prolonged lifespan, increased locomotor activity, and reduced neurodegeneration is observed. We conclude that stabilization of the central Abeta alpha-helix counteracts polymerization into toxic assemblies and provides a strategy for development of specific inhibitors of Abeta polymerization.

| S-EPMC2695042 | biostudies-literature

Functional, metal-based crosslinkers for α-helix induction in short peptides.

Project description:Many protein-protein interactions that play a central role in cellular processes involve α-helical domains. Consequently, there has been great interest in developing strategies for stabilizing short peptides in α-helical conformations toward the inhibition and interrogation of protein-protein interactions. Here, we show that tridentate Hybrid Coordination Motifs (HCMs), which consist of a natural (histidine, His) and an unnatural (8-hydroxyquinoline, Quin) metal binding functionality, can bind divalent metal ions with high affinity and thereby induce/stabilize an α-helical configuration in short peptide sequences. The Quin functionality is readily introduced onto peptide platforms both during or after solid-state peptide synthesis, demonstrating the preparative versatility of HCMs. A systematic study involving a series of HCM-bearing peptides has revealed the critical importance of the length of the linkage between the Quin moiety and the peptide backbone as well as the metal coordination geometry in determining the extent of α-helix induction. Through ZnII coordination or modification with ReI(Quin)(CO)3, the HCM-bearing peptides can be rendered luminescent in the visible region, thus showing that HCMs can be exploited to simultaneously introduce structure and functionality into short peptides.

| S-EPMC3800689 | biostudies-literature

An α-Helix-Mimicking 12,13-Helix: Designed α/β/γ-Foldamers as Selective Inhibitors of Protein-Protein Interactions.

Project description:A major current challenge in bioorganic chemistry is the identification of effective mimics of protein secondary structures that act as inhibitors of protein-protein interactions (PPIs). In this work, trans-2-aminocyclobutanecarboxylic acid (tACBC) was used as the key β-amino acid component in the design of α/β/γ-peptides to structurally mimic a native α-helix. Suitably functionalized α/β/γ-peptides assume an α-helix-mimicking 12,13-helix conformation in solution, exhibit enhanced proteolytic stability in comparison to the wild-type α-peptide parent sequence from which they are derived, and act as selective inhibitors of the p53/hDM2 interaction.

| S-EPMC5014220 | biostudies-literature

Distinctive circular dichroism signature for 14-helix-bundle formation by beta-peptides.

Project description:We identify a distinctive circular dichroism (CD) signature for self-assembled 14-helical beta-peptides. Our data show that self-assembly leads to a mimimum at 205 nm, which is distinct from the well-known minimum at 214 nm for a monomeric 14-helix. The onset of assembly is indicated by [theta]205/[theta]214>0.7. Our results will facilitate rapid screening for self-assembling beta-peptides and raise the possibility that far-UV CD will be useful for detecting higher-order structure for other well-folded oligoamide backbones.

| S-EPMC2886586 | biostudies-literature

α,β-Dehydroamino acids in naturally occurring peptides.

Project description:α,β-Dehydroamino acids are naturally occurring non-coded amino acids, found primarily in peptides. The review focuses on the type of α,β-dehydroamino acids, the structure of dehydropeptides, the source of their origin and bioactivity. Dehydropeptides are isolated primarily from bacteria and less often from fungi, marine invertebrates or even higher plants. They reveal mainly antibiotic, antifungal, antitumour, and phytotoxic activity. More than 60 different structures were classified, which often cover broad families of peptides. 37 different structural units containing the α,β-dehydroamino acid residues were shown including various side chains, Z and E isomers, and main modifications: methylation of peptide bond as well as the introduction of ester group and heterocycle ring. The collected data show the relation between the structure and bioactivity. This allows the activity of compounds, which were not studied in this field, but which belong to a larger peptide family to be predicted. A few examples show that the type of the geometrical isomer of the α,β-dehydroamino acid residue can be important or even crucial for biological activity.

| S-EPMC4282715 | 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