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Stapled peptides

Soonsil Hyun, Yoonhwa Choi, Ha Neul Lee, Changki Lee, Donghoon Oh, Dong-Ki Lee, Changjin Lee, Yan Lee, Jaehoon Yu
A hydrocarbon stapled peptide based strategy was used to develop an optimized cell penetrating peptide for siRNA delivery. Various stapled peptides, having amphipathic Leu- and Lys-rich regions, were prepared and their cell penetrating potentials were evaluated. One peptide, stEK, was found to have high cell penetration and siRNA delivery abilities at low nanomolar concentrations. In order to improve its ability to promote gene silencing, stEK was modified by replacing several Lys residues with His moieties...
April 21, 2018: Chemical Science
Robert A Hillman, Jonathan W Nadraws, Michael A Bertucci
Anomalous protein-protein interactions (PPIs) have been correlated to a variety of disease states, such as cancer, infectious disease, neurological disorders, diabetes, endocrine disorders and cardiovascular disease. Stapled peptides are an emerging intervention for these PPIs due to their improved structural rigidity and pharmacokinetic properties relative to unstapled peptides. This review details the most recent advances in the field of stapled peptide therapeutics, including the increasing variety of PPIs being targeted and types of peptide staples being employed...
May 17, 2018: Current Topics in Medicinal Chemistry
(no author information available yet)
A p53-stapled peptide, ALRN-6924, blocks binding to MDMX and MDM2 to activate p53.
April 20, 2018: Cancer Discovery
Matthew D Lebar, Jeffrey W Cary, Rajtilak Majumdar, Carol H Carter-Wientjes, Brian M Mack, Qijian Wei, Valdet Uka, Sarah De Saeger, José Diana Di Mavungu
Aspergillus flavus can colonize important food staples and produce aflatoxins, a group of toxic and carcinogenic secondary metabolites. Previous in silico analysis of the A. flavus genome revealed 56 gene clusters predicted to be involved in the biosynthesis of secondary metabolites. A. flavus secondary metabolites produced during infection of maize seed are of particular interest, especially with respect to their roles in the biology of the fungus. A predicted nonribosomal peptide synthetase-like (NRPS-like) gene, designated asaC (AFLA_023020), present in the uncharacterized A...
April 16, 2018: Fungal Genetics and Biology: FG & B
Naomi S Robertson, David R Spring
Protein⁻protein interactions (PPIs) are tremendously important for the function of many biological processes. However, because of the structure of many protein⁻protein interfaces (flat, featureless and relatively large), they have largely been overlooked as potential drug targets. In this review, we highlight the current tools used to study the molecular recognition of PPIs through the use of different peptidomimetics, from small molecules and scaffolds to peptides. Then, we focus on constrained peptides, and in particular, ways to constrain α-helices through stapling using both one- and two-component techniques...
April 19, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Surbhi Garg, Gayathri S Singaraju, Sunanda Yengkhom, Sabyasachi Rakshit
Polyproteins, individual protein units joined covalently in tandem, have been evolved as a promising tool for measuring the dynamic folding of bio-macromolecules in single-molecule force spectroscopy. However, the synthetic routes of preparing polyproteins have been a bottleneck, and urge for developing in-vitro methods to knit individual protein units covalently into polyprotein. Employing two enzymes of orthogonal functionalities periodically in sequence, we synthesized monodispersed polyproteins on a solid surface...
April 19, 2018: Bioconjugate Chemistry
Luis A Carvajal, Daniela Ben Neriah, Adrien Senecal, Lumie Benard, Victor Thiruthuvanathan, Tatyana Yatsenko, Swathi-Rao Narayanagari, Justin C Wheat, Tihomira I Todorova, Kelly Mitchell, Charles Kenworthy, Vincent Guerlavais, D Allen Annis, Boris Bartholdy, Britta Will, Jesus D Anampa, Ioannis Mantzaris, Manuel Aivado, Robert H Singer, Robert A Coleman, Amit Verma, Ulrich Steidl
The tumor suppressor p53 is often inactivated via its interaction with endogenous inhibitors mouse double minute 4 homolog (MDM4 or MDMX) or mouse double minute 2 homolog (MDM2), which are frequently overexpressed in patients with acute myeloid leukemia (AML) and other cancers. Pharmacological disruption of both of these interactions has long been sought after as an attractive strategy to fully restore p53-dependent tumor suppressor activity in cancers with wild-type p53. Selective targeting of this pathway has thus far been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX...
April 11, 2018: Science Translational Medicine
Tomi K Sawyer, Anthony W Partridge, Hung Yi Kristal Kaan, Yu-Chi Juang, Shuhui Lim, Charles Johannes, Tsz Ying Yuen, Chandra Verma, Srinivasaraghavan Kannan, Pietro Aronica, Yaw Sing Tan, Brad Sherborne, Sookhee Ha, Jerome Hochman, Shiying Chen, Laura Surdi, Andrea Peier, Berengere Sauvagnat, Peter J Dandliker, Christopher J Brown, Simon Ng, Fernando Ferrer, David P Lane
Macrocyclic α-helical peptides have emerged as a compelling new therapeutic modality to tackle targets confined to the intracellular compartment. Within the scope of hydrocarbon-stapling there has been significant progress to date, including the first stapled α-helical peptide to enter into clinical trials. The principal design concept of stapled α-helical peptides is to mimic a cognate (protein) ligand relative to binding its target via an α-helical interface. However, it was the proclivity of such stapled α-helical peptides to exhibit cell permeability and proteolytic stability that underscored their promise as unique macrocyclic peptide drugs for intracellular targets...
March 16, 2018: Bioorganic & Medicinal Chemistry
A Held, A Glas, L Dietrich, M Bollmann, K Brandstädter, T N Grossmann, C H Lohmann, T Pap, J Bertrand
OBJECTIVE: The canonical Wnt signaling pathway has been shown to be involved in regulating chondrocyte hypertrophic differentiation during OA. The aim of this study was to test the therapeutic potential of two stapled peptide canonical Wnt inhibitors - SAH-Bcl9 and StAx-35R - in preventing Wnt induced cartilage changes in OA. METHODS: Primary neonatal murine chondrocytes and cartilage explants from OA patients undergoing total joint replacement for knee OA, were used for microscopy to determine matrix and cell penetrating capacity of FITC-tagged SAH-Bcl9 and StAx-35R peptides...
March 17, 2018: Osteoarthritis and Cartilage
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.
April 6, 2018: Organic Letters
Peng-Yu 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 intestinal inflammation. Despite being efficacious in a variety of animal models of disease, its therapeutic potential is hampered 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...
April 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, and although 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...
April 12, 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, thus 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 by 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 1, 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...
April 10, 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...
April 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...
March 15, 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...
March 8, 2018: Journal of Medicinal Chemistry
Koki Sakagami, Toshihiro Masuda, Kenichi Kawano, Shiroh Futaki
All-hydrocarbon stapled peptides make up a promising class of protein-protein interaction regulators; their potential therapeutic benefit arises because they have a high binding affinity and specificity for 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...
March 5, 2018: Molecular Pharmaceutics
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