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Stapled peptide

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 the cell-permeable, hydrocarbon-stapled synthetic peptide SAHM1 was results in genome-wide suppression of Notch-activated genes in leukemic cells and other models. However, efficacy of SAHM1 in allergic asthma models has remained unexplored. OBJECTIVE: We aimed to investigate 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
Alissa J Kamens, Kaley M Mientkiewicz, Robyn J Eisert, Jenna A Walz, Charles R Mace, Joshua A Kritzer
Recycling of receptors from the endosomal recycling compartment to the plasma membrane is a critical cellular process, and recycling is particularly important for maintaining invasiveness in solid tumors. In this work, we continue our efforts to inhibit EHD1, a critical adaptor protein involved in receptor recycling. We applied a diversity-oriented macrocyclization approach to produce cyclic peptides with varied conformations, but that each contain a motif that binds to the EH domain of EHD1. Screening these uncovered several new inhibitors for EHD1's EH domain, the most potent of which bound with a Kd of 3...
September 18, 2017: Bioorganic & Medicinal Chemistry
Shreya Mitra, Jeffrey E Montgomery, Matthew J Kolar, Gang Li, Kang J Jeong, Bo Peng, Gregory L Verdine, Gordon B Mills, Raymond E Moellering
Recent evidence has established a role for the small GTPase RAB25, as well as related effector proteins, in enacting both pro-oncogenic and anti-oncogenic phenotypes in specific cellular contexts. Here we report the development of all-hydrocarbon stabilized peptides derived from the RAB-binding FIP-family of proteins to target RAB25. Relative to unmodified peptides, optimized stapled peptides exhibit increased structural stability, binding affinity, cell permeability, and inhibition of RAB25:FIP complex formation...
September 22, 2017: Nature Communications
Marco J Klein, Samuel Schmidt, Parvesh Wadhwani, Jochen Bürck, Johannes Reichert, Sergii Afonin, Marina Berditsch, Tim Schober, Roland Brock, Manfred Kansy, Anne S Ulrich
Stapling of side chains to stabilize an α-helical structure has been generally associated with an increased uptake of CPPs. Here, we compare four amphiphilic stapled peptides with their linear counterparts in terms of their membrane binding and conformational features in order to correlate these with uptake efficiency and toxicological effects. The impact of lactam stapling was found to vary strongly with regard to the different aspects of peptide-membrane interactions. Nearly all stapled peptides caused less membrane perturbation (vesicle leakage, hemolysis, bacterial lysis) than their linear counterparts...
October 12, 2017: Journal of Medicinal Chemistry
Melody D Fulton, Laura E Hanold, Zheng Ruan, Sneha Patel, Aaron M Beedle, Natarajan Kannan, Eileen J Kennedy
Although EGFR is a highly sought-after drug target, inhibitor resistance remains a challenge. As an alternative strategy for kinase inhibition, we sought to explore whether allosteric activation mechanisms could effectively be disrupted. The kinase domain of EGFR forms an atypical asymmetric dimer via head-to-tail interactions and serves as a requisite for kinase activation. The kinase dimer interface is primarily formed by the H-helix derived from one kinase monomer and the small lobe of the second monomer...
September 5, 2017: Bioorganic & Medicinal Chemistry
Mohammad Abid, Yogesh A Sonawane, Jacob I Contreras, Sandeep Rana, Amarnath Natarajan
BACKGROUND: Anti-apoptotic members of the Bcl-2 family of proteins are upregulated in a majority of cancers and are potential therapeutic targets. Fragment-based design led to the development of clinical candidates that target Bcl-xL/Bcl-2. Although these Bcl-xL/Bcl-2 inhibitors showed promise in pre-clinical studies, resistance was observed to several Bcl-xL inhibitors, when used alone. This has been attributed to the over-expression of Mcl-1, another member of the Bcl-2 family of proteins...
September 11, 2017: Current Medicinal Chemistry
Mark Klein
Protein-protein interactions are predominant in the workings of all cells. Until now, there have been a few successes in targeting protein-protein interactions with small molecules. Peptides may overcome some of the challenges of small molecules in disrupting protein-protein interactions. However, peptides present a new set of challenges in drug discovery. Thus, the study of the stabilization of helical peptides has been extensive. Areas covered: Several technological approaches to helical peptide stabilization have been studied...
November 2017: Expert Opinion on Drug Discovery
Hui Ling Ko, Tze Hau Lam, Huijin Ng, Jiaying Toh, Liang Wei Wang, Ee Chee Ren
BACKGROUND & AIMS: The Hepatitis B Virus (HBV) may gain entry into non-liver cells but does not actively replicate in them. We investigated the possibility that these cells possess mechanisms that block HBV core promoter (HBVCP) transcription, specifically absent in liver cells, which together with other liver-specific mechanisms, such as sodium-taurocholate cotransporting polypeptide-mediated entry, enable liver cells to effectively produce HBV. METHODS: Liver and non-liver cell lines were screened for their capacity to activate the HBVCP and synthesize pre-genomic RNA (pgRNA)...
September 5, 2017: Journal of Hepatology
Zhihong Li, Rong Huang, Hongtao Xu, Jiakang Chen, Yuexiong Zhan, Xianhao Zhou, Hongli Chen, Biao Jiang
A new class of N-phenyl-divinylsulfonamides which can be easily prepared have been successfully developed and utilized as efficient linkers in the field of disulfide bond modification. Functional divinylsulfonamides provide opportunities for the specific introduction of various functionalities, including affinity probes, fluorescent tags, and drugs, into peptides.
September 7, 2017: Organic Letters
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