scholarly journals Functionalised staple linkages for modulating the cellular activity of stapled peptides

2014 ◽  
Vol 5 (5) ◽  
pp. 1804-1809 ◽  
Author(s):  
Yu Heng Lau ◽  
Peterson de Andrade ◽  
Soo-Tng Quah ◽  
Maxim Rossmann ◽  
Luca Laraia ◽  
...  
Keyword(s):  
Cellular Activity ◽  
Stapled Peptides ◽  
Synthetic Strategy ◽  
P53 Peptides

A divergent synthetic strategy for generating helical p53 peptides bearing functionalised staple linkages, allowing for efficient optimisation of cellular activity.

Selective Targeting of the p53-hDM2 Interaction Using Hydrocarbon-Stapled p53 Peptides.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 525-525
Author(s):  
Federico Bernal ◽  
Loren D. Walensky ◽  
Andrew F. Tyler ◽  
Stanley J. Korsmeyer ◽  
Gregory L. Verdine
Keyword(s):  
Tumor Suppressor ◽  
Cancer Cells ◽  
Critical Role ◽  
Cell Permeability ◽  
Transactivation Domain ◽  
Binding Interaction ◽  
Stapled Peptides ◽  
P53 Tumor Suppressor ◽  
P53 Peptides

Abstract p53 is a transcription factor that induces cell cycle arrest and apoptosis in response to DNA damage and cellular stress, and thereby plays a critical role in protecting cells from malignant transformation. The E3 ubiquitin ligase hDM2 controls p53 levels through a direct binding interaction that neutralizes p53 transactivation activity, exports nuclear p53, and targets it for degradation via the ubiquitination-proteasomal pathway. Loss of p53 activity, either by deletion, mutation, or hDM2 overexpression, is the most common defect in human cancer. Tumors with preserved expression of wild type p53 are rendered vulnerable to pharmacologic approaches that stabilize and upregulate p53. In this context, hDM2 inhibition has emerged as a validated approach to restore p53 activity and resensitize cancer cells to apoptosis in vitro and in vivo. The inhibition of the p53-hDM2 interaction has been studied intensively with the goal of developing novel therapeutics for cancer. Here we describe the synthesis and evaluation of hydrocarbon-stapled α-helical peptides based on the transactivation domain of the p53 tumor suppressor protein. Select p53 stapled peptides exhibit subnanomolar binding to hDM2, displaying the highest affinity hDM2 binders reported to date. We find that these structurally-stabilized peptides are resistant to proteolysis and exhibit cell permeability as documented by flow cytometry and confocal microscopy analyses. In vivo binding of p53 stapled peptides to nuclear hDM2 is highly specific as demonstrated by co-immunoprecipitation experiments. In response to stapled peptide treatment, we observe upregulation of p53 and its transcriptional targets, including p21 and Bax. As a consequence, the peptides are capable of activating apoptosis in hDM2-overexpressing tumor cells through the p53 tumor suppressor signaling pathway. Thus, we find that hydrocarbon-stapled p53 peptides can trigger apoptosis in cancer cells by effectively modulating the p53-hDM2 protein interaction.

scholarly journals Incorporation of Putative Helix-Breaking Amino Acids in the Design of Novel Stapled Peptides: Exploring Biophysical and Cellular Permeability Properties

Molecules ◽  
2019 ◽  
Vol 24 (12) ◽  
pp. 2292 ◽  
Author(s):  
Anthony W. Partridge ◽  
Hung Yi Kristal Kaan ◽  
Yu-Chi Juang ◽  
Ahmad Sadruddin ◽  
Shuhui Lim ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Binding Affinity ◽  
Amino Acid Substitutions ◽  
Cellular Activity ◽  
Stapled Peptides ◽  
Helical Peptides ◽  
High Affinity ◽  
Cellular Permeability ◽  
Target Binding

Stapled α-helical peptides represent an emerging superclass of macrocyclic molecules with drug-like properties, including high-affinity target binding, protease resistance, and membrane permeability. As a model system for probing the chemical space available for optimizing these properties, we focused on dual Mdm2/MdmX antagonist stapled peptides related to the p53 N-terminus. Specifically, we first generated a library of ATSP-7041 (Chang et al., 2013) analogs iteratively modified by L-Ala and D-amino acids. Single L-Ala substitutions beyond the Mdm2/(X) binding interfacial residues (i.e., Phe3, Trp7, and Cba10) had minimal effects on target binding, α-helical content, and cellular activity. Similar binding affinities and cellular activities were noted at non-interfacial positions when the template residues were substituted with their d-amino acid counterparts, despite the fact that d-amino acid residues typically ‘break’ right-handed α-helices. d-amino acid substitutions at the interfacial residues Phe3 and Cba10 resulted in the expected decreases in binding affinity and cellular activity. Surprisingly, substitution at the remaining interfacial position with its d-amino acid equivalent (i.e., Trp7 to d-Trp7) was fully tolerated, both in terms of its binding affinity and cellular activity. An X-ray structure of the d-Trp7-modified peptide was determined and revealed that the indole side chain was able to interact optimally with its Mdm2 binding site by a slight global re-orientation of the stapled peptide. To further investigate the comparative effects of d-amino acid substitutions we used linear analogs of ATSP-7041, where we replaced the stapling amino acids by Aib (i.e., R84 to Aib4 and S511 to Aib11) to retain the helix-inducing properties of α-methylation. The resultant analog sequence Ac–Leu–Thr–Phe–Aib–Glu–Tyr–Trp–Gln–Leu–Cba–Aib–Ser–Ala–Ala–NH2 exhibited high-affinity target binding (Mdm2 Kd = 43 nM) and significant α-helicity in circular dichroism studies. Relative to this linear ATSP-7041 analog, several d-amino acid substitutions at Mdm2(X) non-binding residues (e.g., d-Glu5, d-Gln8, and d-Leu9) demonstrated decreased binding and α-helicity. Importantly, circular dichroism (CD) spectroscopy showed that although helicity was indeed disrupted by d-amino acids in linear versions of our template sequence, stapled molecules tolerated these residues well. Further studies on stapled peptides incorporating N-methylated amino acids, l-Pro, or Gly substitutions showed that despite some positional dependence, these helix-breaking residues were also generally tolerated in terms of secondary structure, binding affinity, and cellular activity. Overall, macrocyclization by hydrocarbon stapling appears to overcome the destabilization of α-helicity by helix breaking residues and, in the specific case of d-Trp7-modification, a highly potent ATSP-7041 analog (Mdm2 Kd = 30 nM; cellular EC50 = 600 nM) was identified. Our findings provide incentive for future studies to expand the chemical diversity of macrocyclic α-helical peptides (e.g., d-amino acid modifications) to explore their biophysical properties and cellular permeability. Indeed, using the library of 50 peptides generated in this study, a good correlation between cellular permeability and lipophilicity was observed.

The effects of Cyclosporin-A (CYA) on the Ultrastructure of Gingival Mast Cells (GMC) in Behcet's disease (BD)

1990 ◽  
Vol 48 (3) ◽  
pp. 358-359
Author(s):  
Oktay Arda ◽  
Ulkü Noyan ◽  
Selgçk Yilmaz ◽  
Mustafa Taşyürekli ◽  
İsmail Seçkin ◽  
...  
Keyword(s):  
Unknown Etiology ◽  
Control Group ◽  
Target Cells ◽  
Gingival Hyperplasia ◽  
Cellular Activity ◽  
Direct Relation ◽  
Immune Disease ◽  
Genital Ulceration ◽  
Functional Changes ◽  
The Third

Turkish dermatologist, H. Beheet described the disease as recurrent triad of iritis, oral aphthous lesions and genital ulceration. Auto immune disease is the recent focus on the unknown etiology which is still being discussed. Among the other immunosupressive drugs, CyA included in it's treatment newly. One of the important side effects of this drug is gingival hyperplasia which has a direct relation with the presence of teeth and periodontal tissue. We are interested in the ultrastructure of immunocompetent target cells that were affected by CyA in BD.Three groups arranged in each having 5 patients with BD. Control group was the first and didn’t have CyA treatment. Patients who had CyA, but didn’t show gingival hyperplasia assembled the second group. The ones displaying gingival hyperplasia following CyA therapy formed the third group. GMC of control group and their granules are shown in FIG. 1,2,3. GMC of the second group presented initiation of supplementary cellular activity and possible maturing functional changes with the signs of increased number of mitochondria and accumulation of numerous dense cored granules next to few normal ones, FIG. 4,5,6.

The cellular activity of cucurbitacin I is inhibited by glycosylation

Planta Medica ◽  
2014 ◽  
Vol 80 (16) ◽  
Author(s):  
MS Hassoun ◽  
MJ Clément ◽  
M Cailleret ◽  
N Jarroux ◽  
I Hamdi ◽  
...  
Keyword(s):  
Cellular Activity

Generation of Phosphoranyl Radicals via Photoredox Catalysis Enables Voltage–Independent Activation of Strong C–O Bonds

2018 ◽  
Author(s):  
Erin Stache ◽  
Alyssa B. Ertel ◽  
Tomislav Rovis ◽  
Abigail G. Doyle
Keyword(s):  
Carboxylic Acids ◽  
Functional Groups ◽  
Single Step ◽  
Direct Access ◽  
Photoredox Catalysis ◽  
Acyl Radical ◽  
Synthetic Strategy ◽  
Acyl Radicals ◽  
Benzyl Radicals ◽  
Aliphatic Carboxylic Acids

Alcohols and carboxylic acids are ubiquitous functional groups found in organic molecules that could serve as radical precursors, but C–O bonds remain difficult to activate. We report a synthetic strategy for direct access to both alkyl and acyl radicals from these ubiquitous functional groups via photoredox catalysis. This method exploits the unique reactivity of phosphoranyl radicals, generated from a polar/SET crossover between a phosphine radical cation and an oxygen centered nucleophile. We first show the desired reactivity in the reduction of benzylic alcohols to the corresponding benzyl radicals with terminal H-atom trapping to afford the deoxygenated product. Using the same method, we demonstrate access to synthetically versatile acyl radicals which enables the reduction of aromatic and aliphatic carboxylic acids to the corresponding aldehydes with exceptional chemoselectivity. This protocol also transforms carboxylic acids to heterocycles and cyclic ketones via intramolecular acyl radical cyclizations to forge new C–O, C–N and C–C bonds in a single step.

Synthesis of Conjugated Triynes via Alkyne Metathesis

2019 ◽  
Author(s):  
Idriss Curbet ◽  
Sophie Colombel-Rouen ◽  
Romane Manguin ◽  
Anthony Clermont ◽  
Alexandre Quelhas ◽  
...  
Keyword(s):  
Steric Hindrance ◽  
High Selectivity ◽  
Alkyne Metathesis ◽  
Cross Metathesis ◽  
Synthetic Strategy ◽  
Sterically Hindered ◽  
Site Selective

<div> <div> <div> <div> <p>The synthesis of conjugated triynes by molybdenum-catalyzed alkyne metathesis is reported. Strategic to the success of this approach is the utilization of sterically-hindered diynes that allowed for the site- selective alkyne metathesis to produce the desired con- jugated triyne products. The steric hindrance of alkyne moiety was found to be crucial in preventing the for- mation of diyne byproducts. This novel synthetic strategy was amenable to self- and cross-metathesis providing straightforward access to the corresponding symmetrical and dissymmetrical triynes with high selectivity. </p> </div> </div> </div> </div>

Computationally Augmented Retrosynthesis: Total Synthesis of Paspaline A and Emindole PB

2018 ◽  
Author(s):  
Timothy Newhouse ◽  
Daria E. Kim ◽  
Joshua E. Zweig
Keyword(s):  
Chemical Synthesis ◽  
Total Synthesis ◽  
Small Molecules ◽  
First Principles ◽  
Quantum Chemical ◽  
Computational Analysis ◽  
Empirical Evaluation ◽  
Synthetic Strategy ◽  
Catalyzed Reactions ◽  
Enzyme Catalyzed Reactions

The diverse molecular architectures of terpene natural products are assembled by exquisite enzyme-catalyzed reactions. Successful recapitulation of these transformations using chemical synthesis is hard to predict from first principles and therefore challenging to execute. A means of evaluating the feasibility of such chemical reactions would greatly enable the development of concise syntheses of complex small molecules. Herein, we report the computational analysis of the energetic favorability of a key bio-inspired transformation, which we use to inform our synthetic strategy. This approach was applied to synthesize two constituents of the historically challenging indole diterpenoid class, resulting in a concise route to (–)-paspaline A in 9 steps from commercially available materials and the first pathway to and structural confirmation of emindole PB in 13 steps. This work highlights how traditional retrosynthetic design can be augmented with quantum chemical calculations to reveal energetically feasible synthetic disconnections, minimizing time-consuming and expensive empirical evaluation.

Synthesis of Elaborate Benzofuran-2-Carboxamide Derivatives Through a Combination of 8-Aminoquinoline Directed C–H Arylations and Transamidations

2019 ◽  
Author(s):  
Michael Oschmann ◽  
Linus Johansson Holm ◽  
Oscar Verho
Keyword(s):  
Small Molecule ◽  
High Efficiency ◽  
Synthetic Strategy ◽  
Small Molecule Screening ◽  
Physiological Properties ◽  
Wide Range ◽  
Directing Group ◽  
Synthetic Sequence

Benzofurans are everywhere in nature and they have been extensively studied by medicinal chemists over the years because of their chemotherapeutic and physiological properties. Herein, we describe a strategy that can be used to access elaborate benzo-2-carboxamide derivatives, which involves a synthetic sequence of 8-aminoquinoline directed C–H arylations followed by transamidations. For the directed C–H arylations, Pd catalysis was used to install a wide range of aryl and heteroaryl substituents at the C3 position of the benzofuran scaffold in high efficiency. Directing group cleavage and further diversification of the C3-arylated benzofuran products were then achieved in a single synthetic operation through the utilization of a two-step transamidation protocol. By bocylating the 8-aminoquinoline amide moiety of these products, it proved possible to activate them towards aminolysis with different amine nucleophiles. Interestingly, this aminolysis reaction was found to proceed efficiently without the need of any additional catalyst or additive. Given the high efficiency and modularity of this synthetic strategy, it constitute a very attractive approach for generating structurally-diverse collections of benzofuran derivatives for small molecule screening.

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