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Stapled peptide

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https://www.readbyqxmd.com/read/28921993/lactam-stapled-cell-penetrating-peptides-cell-uptake-and-membrane-binding-properties
#1
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 4 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...
September 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28911855/conformationally-constrained-peptides-target-the-allosteric-kinase-dimer-interface-and-inhibit-egfr-activation
#2
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
https://www.readbyqxmd.com/read/28901269/recent-advances-in-cancer-drug-development-targeting-induced-myeloid-cell-leukemia-1-mcl-1-differentiation-protein
#3
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
https://www.readbyqxmd.com/read/28889766/stabilized-helical-peptides-overview-of-the-technologies-and-its-impact-on-drug-discovery
#4
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...
September 9, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28887167/identification-of-slug-and-sox7-as-transcriptional-repressors-binding-to-the-hepatitis-b-virus-core-promoter
#5
Hui Ling Ko, Tze Hau Lam, Huijin Ng, Jiaying Toh, Liang Wei Wang, Ee Chee Ren
BACKGROUND & AIMS: The Hepatitis B Virus (HBV) is carried in many non-liver cell types but does not actively replicate in them. We investigated the possibility that these cells possess HBVCP transcription inhibitory mechanisms specifically absent in liver cells, which together with other liver-specific mechanisms such as NTCP-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 pgRNA...
September 5, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28880566/divinylsulfonamides-as-specific-linkers-for-stapling-disulfide-bonds-in-peptides
#6
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
https://www.readbyqxmd.com/read/28876512/effect-of-stapling-architecture-on-physiochemical-properties-and-cell-permeability-of-stapled-%C3%AE-helical-peptides-a-comparative-study
#7
Yuan Tian, Yanhong Jiang, Jingxu Li, Dongyuan Wang, Hui Zhao, Zigang Li
Stapled peptides emerged as a new class of targeting molecules of high binding affinity and specificity for intracellular undruggable targets. Their ability to penetrate cell membranes were exceptionally intriguing to the field, yet elusively and controversially discussed. To understand the effect of stapling architectures on their physiochemical properties and to aid in promoting their cell permeability, we report herein a comparative study on physiochemical properties and cell permeability of stapled α-helical peptides with different types of cross-links...
September 6, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28873199/cloning-and-functional-characterization-of-the-hbsyr1-gene-encoding-a-syntaxin-related-protein-in-tibetan-hulless-barley-hordeum-vulgare-l-var-nudum-hk-f
#8
Q J Xu, Y L Wang, Z X Wei, H J Yuan, X Q Zeng, N Tashi
Tibetan barley is a staple food for the natives of Qinghai-Tibet Plateau. Drought causes a reduction in barley production. In this study, the full-length cDNA of a gene encoding a syntaxin-associated protein was cloned from the leaves of a drought-resistant variety of barley, "Himalaya 10"; its expression was evaluated during drought stress and rehydration via real-time PCR. The cloned HbSYR1 cDNA sequence was 1300 bp in length, and included an 840-bp open reading frame that encoded 279 amino acids. Sequence analysis predicted the molecular weight of the encoded protein to be 42...
August 31, 2017: Genetics and Molecular Research: GMR
https://www.readbyqxmd.com/read/28833783/intramolecular-cyclization-of-the-antimicrobial-peptide-polybia-mpi-with-triazole-stapling-influence-on-stability-and-bioactivity
#9
Beijun Liu, Wei Zhang, Sanhu Gou, Haifeng Huang, Jia Yao, Zhibin Yang, Hui Liu, Chao Zhong, Beiyin Liu, Jingman Ni, Rui Wang
Cationic antimicrobial peptides have attracted increasing attention as a novel class of antibiotics to treat infectious diseases caused by pathogenic bacteria. However, susceptibility to protease is a shortcoming in their development. Cyclization is one approach to increase the proteolytic resistance of peptides. Therefore, to improve the proteolytic resistance of Polybia-MPI, we have synthesized the MPI cyclic analogs C-MPI-1 (i-to-i+4) and C-MPI-2 (i-to-i+6) by copper(I)-catalyzed azide-alkyne cycloaddition...
August 23, 2017: Journal of Peptide Science: An Official Publication of the European Peptide Society
https://www.readbyqxmd.com/read/28815832/targeting-the-genome-stability-hub-ctf4-by-stapled-peptide-design
#10
Yuteng Wu, Fabrizio Villa, Joseph Maman, Yu Heng Lau, Lina Dobnikar, Aline C Simon, Karim Labib, David R Spring, Luca Pellegrini
The exploitation of synthetic lethality by small-molecule targeting of pathways that maintain genomic stability is an attractive chemotherapeutic approach. The Ctf4/AND-1 protein hub, which links DNA replication, repair, and chromosome segregation, represents a novel target for the synthetic lethality approach. Herein, we report the design, optimization, and validation of double-click stapled peptides encoding the Ctf4-interacting peptide (CIP) of the replicative helicase subunit Sld5. By screening stapling positions in the Sld5 CIP, we identified an unorthodox i,i+6 stapled peptide with improved, submicromolar binding to Ctf4...
August 17, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28757184/cell-permeable-stapled-peptide-inhibitor-of-wnt-signaling-that-targets-%C3%AE-catenin-protein-protein-interactions
#11
Laura Dietrich, Bernd Rathmer, Kenneth Ewan, Tanja Bange, Stefan Heinrichs, Trevor C Dale, Dennis Schade, Tom N Grossmann
The Wnt signaling pathway plays a critical role in cell proliferation and differentiation, thus it is often associated with diseases such as cancers. Unfortunately, although attractive, developing anti-cancer strategy targeting Wnt signaling has been challenging given that the most attractive targets are involved in protein-protein interactions (PPIs). Here, we develop a stapled peptide inhibitor that targets the interaction between β-catenin and T cell factor/lymphoid enhancer-binding factor transcription factors, which are crucially involved in Wnt signaling...
August 17, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28749659/in-situ-methylene-capping-a-general-strategy-for-efficient-stereoretentive-catalytic-olefin-metathesis-the-concept-methodological-implications-and-applications-to-synthesis-of-biologically-active-compounds
#12
Chaofan Xu, Xiao Shen, Amir H Hoveyda
In situ methylene capping is introduced as a practical and broadly applicable strategy that can expand the scope of catalyst-controlled stereoselective olefin metathesis considerably. By incorporation of commercially available Z-butene together with robust and readily accessible Ru-based dithiolate catalysts developed in these laboratories, a large variety of transformations can be made to proceed with terminal alkenes, without the need for a priori synthesis of a stereochemically defined disubstituted olefin...
July 27, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28713567/genetically-engineered-bananas-resistant-to-xanthomonas-wilt-disease-and-nematodes
#13
REVIEW
Leena Tripathi, Howard Atkinson, Hugh Roderick, Jerome Kubiriba, Jaindra N Tripathi
Banana is an important staple food crop feeding more than 100 million Africans, but is subject to severe productivity constraints due to a range of pests and diseases. Banana Xanthomonas wilt caused by Xanthomonas campestris pv. musacearum is capable of entirely destroying a plantation while nematodes can cause losses up to 50% and increase susceptibility to other pests and diseases. Development of improved varieties of banana is fundamental in order to tackle these challenges. However, the sterile nature of the crop and the lack of resistance in Musa germplasm make improvement by traditional breeding techniques either impossible or extremely slow...
May 2017: Food and energy security
https://www.readbyqxmd.com/read/28705263/antiviral-activity-of-dual-acting-hydrocarbon-stapled-peptides-against-hiv-1-predominantly-circulating-in-china
#14
Yan Wang, Francesca Curreli, Wei Si Xu, Zhen Peng Li, De Sheng Kong, Li Ren, Kun Xue Hong, Shi Bo Jiang, Yi Ming Shao, Asim K Debnath, Li Ying Ma
OBJECTIVE: New rationally designed i,i+7-hydrocarbon-stapled peptides that target both HIV-1 assembly and entry have been shown to have antiviral activity against HIV-1 subtypes circulating in Europe and North America. Here, we aimed to evaluate the antiviral activity of these peptides against HIV-1 subtypes predominantly circulating in China. METHODS: The antiviral activity of three i,i+7-hydrocarbon-stapled peptides, NYAD-36, NYAD-67, and NYAD-66, against primary HIV-1 CRF07_BC and CRF01_AE isolates was evaluated in peripheral blood mononuclear cells (PBMCs)...
June 2017: Biomedical and Environmental Sciences: BES
https://www.readbyqxmd.com/read/28701689/lybatides-from-lycium-barbarum-contain-an-unusual-cystine-stapled-helical-peptide-scaffold
#15
Wei Liang Tan, Ka H Wong, Jian Lei, Naoki Sakai, Hong Wei Tan, Rolf Hilgenfeld, James P Tam
Cysteine-rich peptides (CRPs) of 2-6 kDa are generally thermally and proteolytically stable because of their multiple cross-bracing disulfide bonds. Here, we report the discovery and characterization of two novel cystine-stapled CRPs, designated lybatide 1 and 2 (lyba1 and lyba2), from the cortex of Lycium barbarum root. Lybatides, 32 to 33 amino acids in length, are hyperstable and display a novel disulfide connectivity with a cysteine motif of C-C-C-C-CC-CC which contains two pairs of adjacent cysteines (-CC-CC)...
July 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28680267/suppression-of-breast-cancer-metastasis-using-stapled-peptides-targeting-the-wasf-regulatory-complex
#16
John K Cowell, Yong Teng, N George Bendzunas, Roxan Ara, Ali S Arbab, Eileen J Kennedy
The WASF3 gene facilitates the metastatic phenotype, and its inactivation leads to suppression of invasion and metastasis regardless of the genetic background of the cancer cell. This reliance on WASF3 to facilitate metastasis suggests that targeting its function could serve as an effective strategy to suppress metastasis. WASF3 stability and function are regulated by the WASF Regulatory Complex (WRC) of proteins, particularly CYFIP1 and NCKAP1. Knockdown of these proteins in vitro leads to disruption of the WRC and suppression of invasion...
2017: Cancer Growth and Metastasis
https://www.readbyqxmd.com/read/28673313/mdm2-x-inhibitors-under-clinical-evaluation-perspectives-for-the-management-of-hematological-malignancies-and-pediatric-cancer
#17
REVIEW
Veronica Tisato, Rebecca Voltan, Arianna Gonelli, Paola Secchiero, Giorgio Zauli
The two murine double minute (MDM) family members MDM2 and MDMX are at the center of an intense clinical assessment as molecular target for the management of cancer. Indeed, the two proteins act as regulators of P53, a well-known key controller of the cell cycle regulation and cell proliferation that, when altered, plays a direct role on cancer development and progression. Several evidence demonstrated that functional aberrations of P53 in tumors are in most cases the consequence of alterations on the MDM2 and MDMX regulatory proteins, in particular in patients with hematological malignancies where TP53 shows a relatively low frequency of mutation while MDM2 and MDMX are frequently found amplified/overexpressed...
July 3, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28633506/role-of-glucagon-like-peptide-1-and-gastric-inhibitory-peptide-in-anorexia-induction-following-oral-exposure-to-the-trichothecene-mycotoxin-deoxynivalenol-vomitoxin
#18
Hui Jia, Wen-Da Wu, Xi Lu, Jie Zhang, Cheng-Hua He, Hai-Bin Zhang
Deoxynivalenol (DON), which is a Type B trichothecene mycotoxin produced by Fusarium, frequently contaminates cereal staples, such as wheat, barley and corn. DON threatens animal and human health by suppressing food intake and impairing growth. While anorexia induction in mice exposed to DON has been linked to the elevation of the satiety hormones cholecystokinin and peptide YY3-36 in plasma, the effects of DON on the release of other satiety hormones, such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), have not been established...
September 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28603971/enhanced-and-prolonged-cell-penetrating-abilities-of-arginine-rich-peptides-by-introducing-cyclic-%C3%AE-%C3%AE-disubstituted-%C3%AE-amino-acids-with-stapling
#19
Makoto Oba, Masayuki Kunitake, Takuma Kato, Atsushi Ueda, Masakazu Tanaka
Cell-penetrating peptides are receiving increasing attention as drug delivery tools, and the search for peptides with high cell-penetrating ability and negligible cytotoxicity has become a critical research topic. Herein, cyclic α,α-disubstituted α-amino acids were introduced into arginine-rich peptides and an additional staple was provided in the side chain. The peptides designed in the present study showed more enhanced and prolonged cell-penetrating abilities than an arginine nonapeptide due to high resistance to protease and conformationally stable helical structures...
July 19, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28547390/mono-substitution-effects-on-antimicrobial-activity-of-stapled-heptapeptides
#20
Huy X Luong, Do-Hee Kim, Ngoan T Mai, Bong-Jin Lee, Young-Woo Kim
We previously reported a de novo design of antimicrobial heptapeptide helices using Verdine's all-hydrocarbon peptide stapling system. One of the important structure-activity relationships we found from these previous studies was that extending of the hydrophobic face by replacing of alanine with leucine in positon 5 increases antimicrobial activity. In this study, to further improve the activity profile of this peptide series, we investigated the substitution effects of position 5 on conformational and proteolytic stability as well as antimicrobial and hemolytic activity...
May 25, 2017: Archives of Pharmacal Research
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