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Stapled peptide

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
Thomas E Speltz, Jeanne M Danes, Joshua D Stender, Jonna Frasor, Terry W Moore
We and others have proposed that coactivator binding inhibitors, which block the interaction of estrogen receptor and steroid receptor coactivators, may represent a potential class of new breast cancer therapeutics. The development of coactivator binding inhibitors has been limited, however, because many of the current molecules which are active in in vitro and biochemical assays are not active in cell-based assays. Our goal in this work was to prepare a coactivator binding inhibitor active in cellular models of breast cancer...
January 8, 2018: ACS Chemical Biology
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
Kim Quach, Jonathan LaRochelle, Xiao-Han Li, Elizabeth Rhoades, Alanna Schepartz
We have previously reported that miniature proteins containing a distinct array of 5 arginine residues on a folded α-helix - a penta-arg motif - traffic with high efficiency from endosomes into the cytosol and nucleus of mammalian cells. Here we evaluate whether a penta-arg motif can improve the intracellular trafficking of an otherwise impermeant hydrocarbon-stapled peptide, SAH-p53-4(Rho). We prepared a panel of SAH-p53-4(Rho) variants containing penta-arg sequences with different spacings and axial arrangement and evaluated their overall uptake (as judged by flow cytometry) and their intracellular access (as determined by fluorescence correlation spectroscopy, FCS)...
November 7, 2017: Bioorganic & Medicinal Chemistry
Xiao Hu, Yanhua He, Liping Wu, Yujun Hao, Zhenghe Wang, Weiping Zheng
To follow up on our recent discovery of the 18-amino acid all-hydrocarbon [i, i + 4]-stapled p110α[E545K] peptide 1 that was shown to potently block the intracellular p110α[E545K]-IRS1 interaction (a protein-protein interaction uniquely present in cancer cells expressing p110α[E545K]) and the growth of the xenograft tumors formed by cancers harboring this mutation, in the current study we prepared and examined six derivatives of 1, i.e. stapled peptides 2-A, 2-B, 3-A, 3-B, 4-A, 4-B. We found that 2-A, 2-B, 4-A, and 4-B had higher % α-helicity than 1; moreover, the enhanced % α-helicity also led to an enhanced proteolytic stability...
November 11, 2017: Bioorganic & Medicinal Chemistry Letters
Lauren E St Louis, Tayliz M Rodriguez, Marcey L Waters
Peptides are promising scaffolds for use as therapeutics, targeting interactions previously considered to be "undruggable" by small molecules. While short peptides are generally unstructured in solution and rapidly degraded by proteases in the cell cytosol, peptide stapling offers an effective method to both stabilize peptides in a helical structure and increase resistance to proteolytic degradation. Most studies of peptide stapling have focused on residues with i, i + 4 and i, i + 7 spacing, while stapling of residues with i, i + 3 spacing has been understudied...
October 31, 2017: Bioorganic & Medicinal Chemistry
Daniela Kalafatovic, Ernest Giralt
Efficient intracellular drug delivery and target specificity are often hampered by the presence of biological barriers. Thus, compounds that efficiently cross cell membranes are the key to improving the therapeutic value and on-target specificity of non-permeable drugs. The discovery of cell-penetrating peptides (CPPs) and the early design approaches through mimicking the natural penetration domains used by viruses have led to greater efficiency of intracellular delivery. Following these nature-inspired examples, a number of rationally designed CPPs has been developed...
November 8, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Alex KleinJan, Irma Tindemans, Jeffrey E Montgomery, Melanie Lukkes, Marjolein J W de Bruijn, Menno van Nimwegen, Ingrid Bergen, Raymond E Moellering, Henk C Hoogsteden, Louis Boon, Derk Amsen, R W Hendriks
BACKGROUND: The Notch signaling pathway has been implicated in the pathogenesis of allergic airway inflammation. Targeting the active Notch transactivation complex by using the cell-permeable, hydrocarbon-stapled synthetic peptide stapled α-helical peptide derived from mastermind-like 1 (SAHM1) resulted in genome-wide suppression of Notch-activated genes in leukemic cells and other models. However, the efficacy of SAHM1 in allergic asthma models has remained unexplored. OBJECTIVE: We aimed to investigate the therapeutic efficacy of SAHM1 in a house dust mite (HDM)-driven asthma model...
October 27, 2017: Journal of Allergy and Clinical Immunology
Shuang Sun, Ismael Compañón, Nuria Martínez-Sáez, João D Seixas, Omar Boutureira, Francisco Corzana, Gonçalo J L Bernardes
We present a new peptide macrocyclization strategy with an isobutylene graft. The reaction is mild and proceeds rapidly and efficiently both on linear and cyclic peptides. The resulting isobutylene-grafted peptides possess improved passive membrane permeability due to the shielding of the polar backbone of the amides, as demonstrated by NMR and molecular dynamics (MD) simulations. The isobutylene-stapled structures are fully stable in human plasma and in the presence of glutathione. This strategy can be applied to bioactive cyclic peptides such as somatostatin...
November 3, 2017: Chembiochem: a European Journal of Chemical Biology
Yeongju Lee, Heeseok Yoon, Sung-Min Hwang, Min-Kyung Shin, Ji Hoon Lee, Misook Oh, Sin-Hyeog Im, Jaeyoung Song, Hyun-Suk Lim
The complex formation between transcription factors (TFs) and coactivator proteins is required for transcriptional activity, and thus disruption of aberrantly activated TF/coactivator interactions could be an attractive therapeutic strategy. However, modulation of such protein-protein interactions (PPIs) has proven challenging. Here we report a cell-permeable, proteolytically stable, stapled helical peptide directly targeting nuclear receptor coactivator 1 (NCOA1), a coactivator required for the transcriptional activity of signal transducer and activator of transcription 6 (STAT6)...
November 15, 2017: Journal of the American Chemical Society
Huy X Luong, Do-Hee Kim, Bong-Jin Lee, Young-Woo Kim
Polybia-MP1 is a well-known natural antimicrobial peptide isolated from the venom of the social wasp Polybia paulista. A recent study showed that this peptide displays a broad antibacterial spectrum as well as low toxicity to human red blood cells and normal fibroblasts. However, its moderate antimicrobial activity and high susceptibility to protease have been a major hurdle for clinical use. This study examined the possibility of developing biologically more potent, yet metabolically more stable, analogues of MP1 using an emerging technology termed "all-hydrocarbon stapling...
October 26, 2017: Archives of Pharmacal Research
Natalia Estrada-Ortiz, Constantinos G Neochoritis, Aleksandra Twarda-Clapa, Bogdan Musielak, Tad A Holak, Alexander Dömling
Based on a combination of an Ugi four component reaction and a ring closing metathesis, a library of novel artificial macrocyclic inhibitors of the p53-MDM2 interaction was designed and synthesized. These macrocycles, alternatively to stapled peptides, target for the first time the large hydrophobic surface area formed by Tyr67, Gln72, His73, Val93, and Lys94 yielding derivatives with affinity to MDM2 in the nanomolar range. Their binding affinity with MDM2 was evaluated using fluorescence polarization (FP) assay and (1)H-(15)N two-dimensional HSQC nuclear magnetic resonance experiments...
October 12, 2017: ACS Medicinal Chemistry Letters
Sarah E Pease-Raissi, Maria F Pazyra-Murphy, Yihang Li, Franziska Wachter, Yusuke Fukuda, Sara J Fenstermacher, Lauren A Barclay, Gregory H Bird, Loren D Walensky, Rosalind A Segal
Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect of many cancer treatments. The hallmark of CIPN is degeneration of long axons required for transmission of sensory information; axonal degeneration causes impaired tactile sensation and persistent pain. Currently the molecular mechanisms of CIPN are not understood, and there are no available treatments. Here we show that the chemotherapeutic agent paclitaxel triggers CIPN by altering IP3 receptor phosphorylation and intracellular calcium flux, and activating calcium-dependent calpain proteases...
October 11, 2017: Neuron
Claire M Grison, George M Burslem, Jennifer A Miles, Ludwig K A Pilsl, David J Yeo, Zeynab Imani, Stuart L Warriner, Michael E Webb, Andrew J Wilson
The development of constrained peptides for inhibition of protein-protein interactions is an emerging strategy in chemical biology and drug discovery. This manuscript introduces a versatile, rapid and reversible approach to constrain peptides in a bioactive helical conformation using BID and RNase S peptides as models. Dibromomaleimide is used to constrain BID and RNase S peptide sequence variants bearing cysteine (Cys) or homocysteine (hCys) amino acids spaced at i and i + 4 positions by double substitution...
July 1, 2017: Chemical Science
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