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Stapled peptides

Zhihong Li, Rong Huang, Hongtao Xu, Jiakang Chen, Yuexiong Zhan, Xianhao Zhou, Hongli Chen, Biao Jiang
No abstract text is available yet for this article.
March 15, 2018: Organic Letters
Pengyu Yang, Huafei Zou, Candy Lee, Avinash Muppidi, Elizabeth Chao, Qiangwei Fu, Xiaozhou Luo, Danling Wang, Peter G Schultz, Weijun Shen
Glucagon-like peptide 2 (GLP-2) is a hormone that has been shown to stimulate intestinal growth and attenuate intes-tinal inflammation. Despite being efficacious in a variety of animal models of disease, its therapeutic potential is ham-pered by the short half-life in vivo. We now describe a highly potent, stapled long-acting GLP-2 analog, Peptide 10, that has a more than 10-fold longer half-life than teduglutide and improved intestinotrophic and anti-inflammatory effects in mouse models of DSS-induced colitis...
March 12, 2018: Journal of Medicinal Chemistry
Júlia García-Pindado, Tom Willemse, Rebecca Goss, Bert U W Maes, Ernest Giralt, Steven Ballet, Meritxell Teixidó
While revisiting biologically active natural peptides, the importance of the tryptophan residue became clear. In this article, the incorporation of this amino acid, brominated at different positions of the indole ring, into cyclic peptides was successfully achieved. These products demonstrated improved properties in terms of passive diffusion, permeability across membranes, biostability in human serum and cytotoxicity. Moreover, these brominated tryptophans at positions 5, 6, or 7 proved to be compatible as building blocks to prepare bicyclic stapled peptides by performing on-resin Suzuki-Miyaura cross-coupling reactions...
March 12, 2018: Biopolymers
Sean P Cornillie, Benjamin J Bruno, Carol S Lim, Thomas E Cheatham
The oncogenic gene product Bcr-Abl is the principal cause of chronic myeloid leukemia (CML) and though several therapies exist to curb the aberrant kinase activity of Bcr-Abl through targeting of the Abl kinase domain, these therapies are rendered ineffective by frequent mutations in the corresponding gene. It has been demonstrated that a designed protein known as CCmut3 is able to produce a dominant negative inactivating effect on Bcr-Abl kinase by preferentially oligomerizing with the N-terminal coiled-coil oligomerization domain of Bcr-Abl (Bcr-CC) to effectively reduce the oncogenic potential of Bcr-Abl...
March 8, 2018: Journal of Physical Chemistry. B
Philip A Cistrone, Anthony P Silvestri, Jordi C J Hintzen, Philip E Dawson
Peptide macrocycles are widely utilized in the development of high affinity ligands including stapled α-helices. The linear rigidity of a 1,3-diynyl linkage provides an optimal distance (7 Å) between β- carbons of the i, i+4 amino acid side chains, suggesting its utility in stabilizing α-helical structures. Here we report the development of an on-resin strategy for an intramolecular Glaser reaction between two alkyne-terminated side chains using copper chloride, an essential bpy-diol ligand, and diisopropylethylamine, at room temperature...
March 7, 2018: Chembiochem: a European Journal of Chemical Biology
Jacob Rodriguez, Sloane O'Neill, Maciej A Walczak
Review primarily covers from 1995-2018Carbohydrate function, recognized in a multitude of biological processes, provides a precedent for developing carbohydrate surrogates that mimic the structure and function of bioactive compounds. In order to constrain highly flexible oligosaccharides, synthetic tethering techniques like those exemplified by stapled peptides are utilized to varying degrees of success. Naturally occurring constrained carbohydrates, however, exist with noteworthy cytotoxic and chemosensitizing properties...
March 7, 2018: Natural Product Reports
Marta Ruiz-Santaquiteria, Sonia de Castro, Miguel A Toro, Héctor de Lucio, Kilian Jesús Gutiérrez, Pedro A Sánchez-Murcia, María Ángeles Jiménez, Federico Gago, Antonio Jiménez-Ruiz, María-José Camarasa, Sonsoles Velázquez
Trypanothione reductase (TryR) is a well-established target in the search for novel antitrypanosomal and antileishmanial agents. We have previously identified linear and lactam-bridged 13-residue peptides derived from an α-helical region making up part of the dimeric interface of Leishmania infantum TryR (Li-TryR) which prevent trypanothione reduction by disrupting enzyme dimerization. We now show that i,i + 4 side-chain cross-linking with an all-hydrocarbon staple stabilizes the helical structure of these peptides and significantly improves their resistance to protease cleavage relative to previous linear and cyclic lactam analogues...
February 24, 2018: European Journal of Medicinal Chemistry
Lasse Karhu, Janne Weisell, Pauli M Turunen, Teppo O Leino, Henri Pätsi, Henri Xhaard, Jyrki P Kukkonen, Erik A A Wallén
The peptides orexin-A and -B, the endogenous agonists of the orexin receptors, have similar 19-amino-acid C-termini which retain full maximum response as truncated peptides with only marginally reduced potency, while further N-terminal truncations successively reduce the activity. The peptides have been suggested to bind in an α-helical conformation, and truncation beyond a certain critical length is likely to disrupt the overall helical structure. In this study, we set out to stabilize the α-helical conformation of orexin-A15-33 via peptide stapling at four different sites...
February 20, 2018: Peptides
N George Bendzunas, Sabrina Dörfler, Karolin Autenrieth, Daniela Bertinetti, Erik M F Machal, Eileen J Kennedy, Friedrich W Herberg
Generation of the second messenger molecule cAMP mediates a variety of cellular responses which are essential for critical cellular processes. In response to elevated cAMP levels, cAMP dependent protein kinase (PKA) phosphorylates serine and threonine residues on a wide variety of target substrates. In order to enhance the precision and directionality of these signaling events, PKA is localized to discrete locations within the cell by A-kinase anchoring proteins (AKAPs). The interaction between PKA and AKAPs is mediated via an amphipathic α-helix derived from AKAPs which binds to a stable hydrophobic groove formed in the dimerization/docking (D/D) domain of PKA-R in an isoform-specific fashion...
February 12, 2018: Bioorganic & Medicinal Chemistry
Chao Wang, Shuai Xia, Peiyu Zhang, Tianhong Zhang, Weicong Wang, Yangli Tian, Guangpeng Meng, Shibo Jiang, Keliang Liu
The hexameric α-helical coiled-coil formed between the C-terminal and N-terminal heptad repeat (CHR and NHR) regions of class I viral fusion proteins plays an important role in mediating the fusion of the viral and cellular membranes and provides a clear starting point for molecular mimicry that drives viral fusion inhibitor design. Unfortunately, such peptide mimicry of the short α-helical region in the CHR of Middle East respiratory syndrome coronavirus (MERS-CoV) spike protein has been thwarted by the loss of the peptide's native α-helical conformation when taken out of the parent protein structure...
February 21, 2018: Journal of Medicinal Chemistry
Koki Sakagami, Toshihiro Masuda, Kenichi Kawano, Shiroh Futaki
All-hydrocarbon stapled peptides are a promising class of protein-protein interaction regulators; their potential therapeutic benefit arises because they have high binding affinity and specificity to intracellular molecules. The cell permeation efficacy of these peptides is a critical determinant of their bioactivity. However, the factors that determine their cellular uptake remain an active area of research. In this study, we evaluated the effect of stapled (or cross-linked) formation on the cellular uptake of six known all-hydrocarbon stapled peptides...
February 8, 2018: Molecular Pharmaceutics
Raheleh Rezaei Araghi, Gregory H Bird, Jeremy A Ryan, Justin M Jenson, Marina Godes, Jonathan R Pritz, Robert A Grant, Anthony Letai, Loren D Walensky, Amy E Keating
Bcl-2 family proteins regulate apoptosis, and aberrant interactions of overexpressed antiapoptotic family members such as Mcl-1 promote cell transformation, cancer survival, and resistance to chemotherapy. Discovering potent and selective Mcl-1 inhibitors that can relieve apoptotic blockades is thus a high priority for cancer research. An attractive strategy for disabling Mcl-1 involves using designer peptides to competitively engage its binding groove, mimicking the structural mechanism of action of native sensitizer BH3-only proteins...
January 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
Dorian Migoń, Damian Neubauer, Wojciech Kamysz
Antimicrobial peptides are promising candidates for anti-infective pharmaceuticals. Unfortunately, because of their low proteolytic and chemical stability, their usage is generally narrowed down to topical formulations. Until now, numerous approaches to increase peptide stability have been proposed. One of them, peptide hydrocarbon stapling, a modification based on stabilizing peptide secondary structure with a side-chain covalent hydrocarbon bridge, have been successfully applied to many peptides. Moreover, constraining secondary structure of peptides have also been proven to increase their biological activity...
January 12, 2018: Protein Journal
Edward P Harvey, Hyuk-Soo Seo, Rachel M Guerra, Gregory H Bird, Sirano Dhe-Paganon, Loren D Walensky
BCL-2 family proteins are high-priority cancer targets whose structures provide essential blueprints for drug design. Whereas numerous structures of anti-apoptotic BCL-2 protein complexes with α-helical BH3 peptides have been reported, the corresponding panel of apo structures remains incomplete. Here, we report the crystal structure of apo BFL-1 at 1.69-Å resolution, revealing similarities and key differences among unliganded anti-apoptotic proteins. Unlike all other BCL-2 proteins, apo BFL-1 contains a surface-accessible cysteine within its BH3-binding groove, allowing for selective covalent targeting by a NOXA BH3-based stapled peptide inhibitor...
December 6, 2017: Structure
Tracy A Stone, Gregory B Cole, Huong Q Nguyen, Simon Sharpe, Charles M Deber
Cyclization has been recognized as a valuable technique for increasing the efficacy of small molecule and peptide therapeutics. Here we report the application of a hydrocarbon staple to a rationally-designed cationic antimicrobial peptide (CAP) that acquires increased membrane targeting and interaction vs. its linear counterpart. The previously-described CAP, 6K-F17 (KKKKKK-AAFAAWAAFAA-NH2) was used as the backbone for incorporation of an i to i + 4 helical hydrocarbon staple through olefin ring closing metathesis...
October 21, 2017: Bioorganic & Medicinal Chemistry
Serge Zaretsky, Andrei K Yudin
Constrained peptides pose tremendous value in drug discovery. For example, owing to their large surface areas, they offer novel ways at inhibiting protein-protein interactions. As this field has grown, it has become desirable to introduce non-peptidic functionality into these rings to enable differentiated structure activity relationships and improved pharmacokinetic properties. Recent advances in the synthesis of cyclic pseudopeptides include macrocyclization through cysteine alkylation, multicomponent reactions, decarboxylative couplings, and novel stapling chemistry...
December 2017: Drug Discovery Today. Technologies
Francisco Aguilar-Alonso, Amanda L Whiting, Ye Joon Kim, Federico Bernal
Linear ubiquitylation, in which ubiquitin units are covalently linked through N- and C-terminal amino acids, is a unique cellular signaling mechanism. This process is controlled by a single E3 ubiquitin ligase, the linear ubiquitin chain assembly complex (LUBAC), which is composed of three proteins - HOIL-1L, HOIP and SHARPIN. LUBAC is involved in the activation of the canonical NF-κB pathway and has been linked to NF-κB dependent malignancies. In this work, we present HOIP-based stapled alpha-helical peptides designed to inhibit LUBAC through the disruption of the HOIL-1L-HOIP interaction and loss of the functional complex...
December 5, 2017: Bioorganic & Medicinal Chemistry
Sharon Min Qi Chee, Jantana Wongsantichon, Jiawei Siau, Dawn Thean, Fernando Ferrer, Robert C Robinson, David P Lane, Christopher J Brown, Farid J Ghadessy
As primary p53 antagonists, Mdm2 and the closely related Mdm4 are relevant cancer therapeutic targets. We have previously described a series of cell-permeable stapled peptides that bind to Mdm2 with high affinity, resulting in activation of the p53 tumour suppressor. Within this series, highest affinity was obtained by modification of an obligate tryptophan residue to the non-natural L-6-chlorotryptophan. To understand the structural basis for improved affinity we have solved the crystal structure of this stapled peptide (M011) bound to Mdm2 (residues 6-125) at 1...
2017: PloS One
Alessandro Contini, Nicola Ferri, Raffaella Bucci, Maria Giovanna Lupo, Emanuela Erba, Maria Luisa Gelmi, Sara Pellegrino
Rac1 GTPase interaction with guanine nucleotide exchange factor Tiam1 is involved in several cancer types and cardiovascular diseases. Although small molecules interfering with their protein-protein interaction (PPI) were identified and studied, the ability of small peptides and peptide mimics acting as Rac1/Tiam1 PPI inhibitors has not been yet explored. Using computational alanine scanning (CAS), the "hot" interfacial residues have been determined allowing the design of a small library of putative PPI inhibitors...
November 27, 2017: Biopolymers
Ye Wu, Ye-Hua Li, Xiang Li, Yan Zou, Hong-Li Liao, Lei Liu, Ye-Guang Chen, Donald Bierer, Hong-Gang Hu
The all-hydrocarbon peptide stapling strategy has recently been extensively explored in drug discovery. There remains the potential for improvement regarding the retention of the amino acid side chains at the stapled positions. Herein, we describe a new series of amino acids that not only contain the native side chains, but also carry the alkenyl arms that are needed for the ring-closing stapling chemistry. We incorporate the new amino acids into a β-catenin-binding domain of Axin (469-482) and develop a new category of stapled peptides with the retention of the native side chains...
November 1, 2017: Chemical Science
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