Browse
Submit Data
Databases
API
Help

Dataset Information

34 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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 ?-amino acid component in the design of ?/?/?-peptides to structurally mimic a native ?-helix. Suitably functionalized ?/?/?-peptides assume an ?-helix-mimicking 12,13-helix conformation in solution, exhibit enhanced proteolytic stability in comparison to the wild-type ?-peptide parent sequence from which they are derived, and act as selective inhibitors of the p53/hDM2 interaction.

SUBMITTER: Grison CM

PROVIDER: S-EPMC5014220 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

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

Grison Claire M CM Miles Jennifer A JA Robin Sylvie S Wilson Andrew J AJ Aitken David J DJ

Angewandte Chemie (International ed. in English) 20160728 37

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 st ...[more]

PMID: 27467859

Similar Datasets

α-Helix-Mimicking Sulfono-γ-AApeptide Inhibitors for p53-MDM2/MDMX Protein-Protein Interactions.

Project description:The use of peptidomimetic scaffolds is a promising strategy for the inhibition of protein-protein interactions (PPIs). Herein, we demonstrate that sulfono-γ-AApeptides can be rationally designed to mimic the p53 α-helix and inhibit p53-MDM2 PPIs. The best inhibitor, with Kd and IC50 values of 26 nM and 0.891 μM toward MDM2, respectively, is among the most potent unnatural peptidomimetic inhibitors disrupting the p53-MDM2/MDMX interaction. Using fluorescence polarization assays, circular dichroism, nuclear magnetic resonance spectroscopy, and computational simulations, we demonstrate that sulfono-γ-AApeptides adopt helical structures resembling p53 and competitively inhibit the p53-MDM2 interaction by binding to the hydrophobic cleft of MDM2. Intriguingly, the stapled sulfono-γ-AApeptides showed promising cellular activity by enhancing p53 transcriptional activity and inducing expression of MDM2 and p21. Moreover, sulfono-γ-AApeptides exhibited remarkable resistance to proteolysis, augmenting their biological potential. Our results suggest that sulfono-γ-AApeptides are a new class of unnatural helical foldamers that disrupt PPIs.

| S-EPMC7025332 | biostudies-literature

Helix formation in preorganized beta/gamma-peptide foldamers: hydrogen-bond analogy to the alpha-helix without alpha-amino acid residues.

Project description:We report the first high-resolution structural data for the beta/gamma-peptide 13-helix (i,i+3 C=O...H-N H-bonds), a secondary structure that is formed by oligomers with a 1:1 alternation of beta- and gamma-amino acid residues. Our characterization includes both crystallographic and 2D NMR data. Previous studies suggested that beta/gamma-peptides constructed from conformationally flexible residues adopt a different helical secondary structure in solution. Our design features preorganized beta- and gamma-residues, which strongly promote 13-helical folding by the 1:1 beta/gamma backbone.

| S-EPMC2904518 | biostudies-other

Inhibition of β-catenin/B cell lymphoma 9 protein-protein interaction using α-helix-mimicking sulfono-γ-AApeptide inhibitors.

Project description:The rational design of α-helix-mimicking peptidomimetics provides a streamlined approach to discover potent inhibitors for protein-protein interactions (PPIs). However, designing cell-penetrating long peptidomimetic scaffolds equipped with various functional groups necessary for interacting with large protein-binding interfaces remains challenging. This is particularly true for targeting β-catenin/BCL9 PPIs. Here we designed a series of unprecedented helical sulfono-γ-AApeptides that mimic the binding mode of the α-helical HD2 domain of B Cell Lymphoma 9 (BCL9). Our studies show that sulfono-γ-AApeptides can structurally and functionally mimic the α-helical domain of BCL9 and selectively disrupt β-catenin/BCL9 PPIs with even higher potency. More intriguingly, these sulfono-γ-AApeptides can enter cancer cells, bind with β-catenin and disrupt β-catenin/BCL9 PPIs, and exhibit excellent cellular activity, which is much more potent than the BCL9 peptide. Furthermore, our enzymatic stability studies demonstrate the remarkable stability of the helical sulfono-γ-AApeptides, with no degradation in the presence of pronase for 24 h, augmenting their biological potential. This work represents not only an example of helical sulfono-γ-AApeptides that mimic α-helix and disrupt protein-protein interactions, but also an excellent example of potent, selective, and cell-permeable unnatural foldameric peptidomimetics that disrupt the β-catenin/BCL9 PPI. The design of helical sulfono-γ-AApeptides may lead to a new strategy to modulate a myriad of protein-protein interactions.

| S-EPMC6561201 | biostudies-literature

Isolated α-turn and incipient γ-helix.

Project description:The unique abilities of homo-oligo-adamantyl peptides to adopt α- and γ-turn conformations are demonstrated by X-ray diffraction, and NMR and FT-IR absorption spectroscopies. Assembled by an Ugi multiple component reaction strategy, N α-formyl-adamantyl tripeptide iso-propyl and tert-butyl amides are respectively found to adopt an isolated α-turn and an incipient γ-helix conformation by X-ray diffraction crystallography. The shortest example of a single α-turn with ideal geometry is observed in the crystalline state. In solution both peptides predominantly assume γ-helical structures.

| S-EPMC6640192 | biostudies-literature

Rational Design and Synthesis of Right-Handed d-Sulfono-γ-AApeptide Helical Foldamers as Potent Inhibitors of Protein-Protein Interactions.

Project description:Novel unprecedented helical foldamers have been effectively designed and synthesized. The homogeneous right-handed d-sulfono-γ-AApeptides represent a new generation of unnatural helical peptidomimetics, which have similar folding conformation to α-peptides, making them an ideal molecular scaffold to design α-helical mimetics. As demonstrated with p53-MDM2 PPI as a model application, the right-handed d-sulfono-γ-AApeptides reveal much-enhanced binding affinity compared to the p53 peptide. The design of d-sulfono-γ-AApeptides may provide a new and alternative strategy to modulate protein-protein interactions.

| S-EPMC8204676 | biostudies-literature

Design, synthesis, and evaluation of an alpha-helix mimetic library targeting protein-protein interactions.

Project description:The design and solution-phase synthesis of an alpha-helix mimetic library as an integral component of a small-molecule library targeting protein-protein interactions are described. The iterative design, synthesis, and evaluation of the candidate alpha-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 x 20 x 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i + 4, i + 7 amino acid side chains of an alpha-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid-liquid extractions for purification on a scale that insures its long-term availability for screening campaigns. Screening of the library for inhibition of MDM2/p53 binding not only identified the lead alpha-helix mimetic upon which the library was based, but also suggests that a digestion of the initial screening results that accompany the use of such a comprehensive library can provide insights into the nature of the interaction (e.g., an alpha-helix mediated protein-protein interaction) and define the key residues and their characteristics responsible for recognition.

| S-EPMC2765553 | biostudies-literature

?/?-Peptide Foldamers Targeting Intracellular Protein-Protein Interactions with Activity in Living Cells.

Project description:Peptides can be developed as effective antagonists of protein-protein interactions, but conventional peptides (i.e., oligomers of l-?-amino acids) suffer from significant limitations in vivo. Short half-lives due to rapid proteolytic degradation and an inability to cross cell membranes often preclude biological applications of peptides. Oligomers that contain both ?- and ?-amino acid residues ("?/?-peptides") manifest decreased susceptibility to proteolytic degradation, and when properly designed these unnatural oligomers can mimic the protein-recognition properties of analogous "?-peptides". This report documents an extension of the ?/?-peptide approach to target intracellular protein-protein interactions. Specifically, we have generated ?/?-peptides based on a "stapled" Bim BH3 ?-peptide, which contains a hydrocarbon cross-link to enhance ?-helix stability. We show that a stapled ?/?-peptide can structurally and functionally mimic the parent stapled ?-peptide in its ability to enter certain types of cells and block protein-protein interactions associated with apoptotic signaling. However, the ?/?-peptide is nearly 100-fold more resistant to proteolysis than is the parent stapled ?-peptide. These results show that backbone modification, a strategy that has received relatively little attention in terms of peptide engineering for biomedical applications, can be combined with more commonly deployed peripheral modifications such as side chain cross-linking to produce synergistic benefits.

| S-EPMC4687753 | biostudies-literature

Characterizing alpha helical properties of Ebola viral proteins as potential targets for inhibition of alpha-helix mediated protein-protein interactions.

Project description:Ebola, considered till recently as a rare and endemic disease, has dramatically transformed into a potentially global humanitarian crisis. The genome of Ebola, a member of the Filoviridae family, encodes seven proteins. Based on the recently implemented software (PAGAL) for analyzing the hydrophobicity and amphipathicity properties of alpha helices (AH) in proteins, we characterize the helices in the Ebola proteome. We demonstrate that AHs with characteristically unique features are involved in critical interactions with the host proteins. For example, the Ebola virus membrane fusion subunit, GP2, from the envelope glycoprotein ectodomain has an AH with a large hydrophobic moment. The neutralizing antibody (KZ52) derived from a human survivor of the 1995 Kikwit outbreak recognizes a protein epitope on this AH, emphasizing the critical nature of this secondary structure in the virulence of the Ebola virus. Our method ensures a comprehensive list of such `hotspots'. These helices probably are or can be the target of molecules designed to inhibit AH mediated protein-protein interactions. Further, by comparing the AHs in proteins of the related Marburg viruses, we are able to elicit subtle changes in the proteins that might render them ineffective to previously successful drugs. Such differences are difficult to identify by a simple sequence or structural alignment. Thus, analyzing AHs in the small Ebola proteome can aid rational design aimed at countering the `largest Ebola epidemic, affecting multiple countries in West Africa' ( http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/index.html).

| S-EPMC4329671 | biostudies-literature

Designed alpha-helical barrels for charge-selective peptide translocation.

Project description:Synthetic alpha-helix based pores for selective sensing of peptides have not been characterized previously. Here, we report large transmembrane pores, pPorA formed from short synthetic alpha-helical peptides of tunable conductance and selectivity for single-molecule sensing of peptides. We quantified the selective translocation kinetics of differently charged cationic and anionic peptides through these synthetic pores at single-molecule resolution. The charged peptides are electrophoretically pulled into the pores resulting in an increase in the dissociation rate with the voltage indicating successful translocation of peptides. More specifically, we elucidated the charge pattern lining the pore lumen and the orientation of the pores in the membrane based on the asymmetry in the peptide-binding kinetics. The salt and pH-dependent measurements confirm the electrostatic dominance and charge selectivity in controlling target peptide interaction with the pores. Remarkably, we tuned the selectivity of the pores to charged peptides by modifying the charge composition of the pores, thus establishing the molecular and electrostatic basis of peptide translocation. We suggest that these synthetic pores that selectively conduct specific ions and biomolecules are advantageous for nanopore proteomics analysis and synthetic nanobiotechnology applications.

| S-EPMC8178987 | biostudies-literature

Acyl Transfer Catalytic Activity in De Novo Designed Protein with N-Terminus of α-Helix As Oxyanion-Binding Site.

Project description:The design of catalytic proteins with functional sites capable of specific chemistry is gaining momentum and a number of artificial enzymes have recently been reported, including hydrolases, oxidoreductases, retro-aldolases, and others. Our goal is to develop a peptide ligase for robust catalysis of amide bond formation that possesses no stringent restrictions to the amino acid composition at the ligation junction. We report here the successful completion of the first step in this long-term project by building a completely de novo protein with predefined acyl transfer catalytic activity. We applied a minimalist approach to rationally design an oxyanion hole within a small cavity that contains an adjacent thiol nucleophile. The N-terminus of the α-helix with unpaired hydrogen-bond donors was exploited as a structural motif to stabilize negatively charged tetrahedral intermediates in nucleophilic addition-elimination reactions at the acyl group. Cysteine acting as a principal catalytic residue was introduced at the second residue position of the α-helix N-terminus in a designed three-α-helix protein based on structural informatics prediction. We showed that this minimal set of functional elements is sufficient for the emergence of catalytic activity in a de novo protein. Using peptide-αthioesters as acyl-donors, we demonstrated their catalyzed amidation concomitant with hydrolysis and proved that the environment at the catalytic site critically influences the reaction outcome. These results represent a promising starting point for the development of efficient catalysts for protein labeling, conjugation, and peptide ligation.

| S-EPMC8012002 | 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