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https://www.readbyqxmd.com/read/28326635/structure-enabled-discovery-of-a-stapled-peptide-inhibitor-to-target-the-oncogenic-transcriptional-repressor-tle1
#1
Sally McGrath, Marcello Tortorici, Ludovic Drouin, Savade Solanki, Lewis Vidler, Isaac Westwood, Peter Gimeson, Rob vanMontfort, Swen Hoelder
TLE1 is an oncogenic transcriptional co-repressor that exerts its repressive effects through binding of transcription factors. Inhibition of this protein-protein interaction represents a putative cancer target but no small molecule inhibitors have been published for this challenging interface. In this manuscript, we report the structure enabled design and synthesis of a constrained peptide inhibitor of TLE1. Our design featured introduction of a four carbon atom linker into the peptide epitope found in many TLE1 binding partners...
March 22, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28315476/comparative-analysis-of-protein-evolution-in-the-genome-of-pre-epidemic-and-epidemic-zika-virus
#2
Arunachalam Ramaiah, Lei Dai, Deisy Contreras, Sanjeev Sinha, Ren Sun, Vaithilingaraja Arumugaswami
Zika virus (ZIKV) causes microcephaly in congenital infection, neurological disorders, and poor pregnancy outcome and no vaccine is available for use in humans or approved. Although ZIKV was first discovered in 1947, the exact mechanism of virus replication and pathogenesis remains unknown. Recent outbreaks of Zika virus in the Americas clearly suggest a human-mosquito cycle or urban cycle of transmission. Understanding the conserved and adaptive features in the evolution of ZIKV genome will provide a hint on the mechanism of ZIKV adaptation to a new cycle of transmission...
March 14, 2017: Infection, Genetics and Evolution
https://www.readbyqxmd.com/read/28273482/orai1-mediated-antimicrobial-secretion-from-pancreatic-acini-shapes-the-gut-microbiome-and-regulates-gut-innate-immunity
#3
Malini Ahuja, Daniella M Schwartz, Mayank Tandon, Aran Son, Mei Zeng, William Swaim, Michael Eckhaus, Victoria Hoffman, Yiyuan Cui, Bo Xiao, Paul F Worley, Shmuel Muallem
The gut microbiome participates in numerous physiologic functions and communicates intimately with the host immune system. Antimicrobial peptides are critical components of intestinal innate immunity. We report a prominent role for antimicrobials secreted by pancreatic acini in shaping the gut microbiome that is essential for intestinal innate immunity, barrier function, and survival. Deletion of the Ca(2+) channel Orai1 in pancreatic acini of adult mice resulted in 60%-70% mortality within 3 weeks. Despite robust activation of the intestinal innate immune response, mice lacking acinar Orai1 exhibited intestinal bacterial outgrowth and dysbiosis, ultimately causing systemic translocation, inflammation, and death...
March 7, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28260497/improved-protein-toxin-delivery-based-on-attempts-systems
#4
Yongzhuo Huang, Victor C Yang, Feng Li, Meong Cheol Shin, Huiyuan Wang, Kyoung Ah Min, Meng Zhang, Yingzhi Chen
Ribosome-inactivating proteins (RIPs) are wildly found in multiple species of plants, bacteria and fungi. As a special family of protein toxins, RIPs can inhibit protein synthesis and induce cell death via inactivating ribosome in eukaryotic cells. Thus, RIPs have been applied for anti-tumor therapy in the past two decades. However, because of poor cell permeability, nonselective mode of action for tumor cells, poor pharmacokinetic profiles and immunogenicity, their clinical application has been severely constrained...
March 1, 2017: Current Drug Targets
https://www.readbyqxmd.com/read/28257168/thioether-derived-macrocycle-for-peptide-secondary-structure-fixation
#5
REVIEW
Yuan Tian, Dan Yang, Xiyang Ye, Zigang Li
Recently, we developed methods to stabilize peptides into various secondary structures, including α-helix, type III turn and β-hairpin via proper thioether based macrocyclization. These conformationally constrained peptidomimetics confer enhanced biophysical properties and provide a valuable avenue towards clinically-relevant therapeutic molecules. In this personal account, thioether-derived macrocyclization methods developed by our group for stabilization of α-helix, type-III β turn and β-hairpin conformations are discussed...
March 3, 2017: Chemical Record: An Official Publication of the Chemical Society of Japan ... [et Al.]
https://www.readbyqxmd.com/read/28240444/precisely-regulated-and-efficient-locking-of-linear-peptides-into-stable-multicyclic-topologies-through-a-one-pot-reaction
#6
Weidong Liu, Yiwu Zheng, Xudong Kong, Christian Heinis, Yibing Zhao, Chuanliu Wu
We report the discovery of a small phenyl molecule with four isosteric thiolate-reactive groups of sequentially varied reactivity. This molecule was exploited in combination with cysteine/penicillamine thiolates of different nucleophilic reactivity for precisely regulated and efficient locking (PROP-locking) of linear peptides into multicyclic topologies through a one-pot reaction. The PROP-locking relies on multistep and sequential thiolate/fluorine nucleophilic substitutions, which is not only rapid but highly specific, thus enabling rapid locking of peptides with high amino acid diversities without protecting groups...
February 27, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28236235/anchordock-for-blind-flexible-docking-of-peptides-to-proteins
#7
Michal Slutzki, Avraham Ben-Shimon, Masha Y Niv
Due to increasing interest in peptides as signaling modulators and drug candidates, several methods for peptide docking to their target proteins are under active development. The "blind" docking problem, where the peptide-binding site on the protein surface is unknown, presents one of the current challenges in the field. AnchorDock protocol was developed by Ben-Shimon and Niv to address this challenge.This protocol narrows the docking search to the most relevant parts of the conformational space. This is achieved by pre-folding the free peptide and by computationally detecting anchoring spots on the surface of the unbound protein...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28186733/utilizing-selenocysteine-for-expressed-protein-ligation-and-bioconjugations
#8
Jun Liu, Qingqing Chen, Sharon Rozovsky
Employing selenocysteine-containing protein fragments to form the amide bond between respective protein fragments significantly extends the current capabilities of the widely used protein engineering method, expressed protein ligation. Selenocysteine-mediated ligation is noteworthy for its high yield and efficiency. However, it has so far been restricted to solid-phase synthesized seleno-peptides and thus constrained by where the selenocysteine can be positioned. Here we employ heterologously expressed seleno-fragments to overcome the placement and size restrictions in selenocysteine-mediated chemical ligation...
February 27, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28185915/targeting-kinase-signaling-pathways-with-constrained-peptide-scaffolds
#9
REVIEW
Laura E Hanold, Melody D Fulton, Eileen J Kennedy
Kinases are amongst the largest families in the human proteome and serve as critical mediators of a myriad of cell signaling pathways. Since altered kinase activity is implicated in a variety of pathological diseases, kinases have become a prominent class of proteins for targeted inhibition. Although numerous small molecule and antibody-based inhibitors have already received clinical approval, several challenges may still exist with these strategies including resistance, target selection, inhibitor potency and in vivo activity profiles...
February 7, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28184219/identification-of-bacterial-surface-antigens-by-screening-peptide-phage-libraries-using-whole-bacteria-cell-purified-antisera
#10
Yun-Fei Hu, Dun Zhao, Xing-Long Yu, Yu-Li Hu, Run-Cheng Li, Meng Ge, Tian-Qi Xu, Xiao-Bo Liu, Hua-Yuan Liao
Bacterial surface proteins can be good vaccine candidates. In the present study, we used polyclonal antibodies purified with intact Erysipelothrix rhusiopthiae to screen phage-displayed random dodecapeptide and loop-constrained heptapeptide libraries, which led to the identification of mimotopes. Homology search of the mimotope sequences against E. rhusiopthiae-encoded ORF sequences revealed 14 new antigens that may localize on the surface of E. rhusiopthiae. When these putative surface proteins were used to immunize mice, 9/11 antigens induced protective immunity...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28167892/selection-of-small-synthetic-antimicrobial-peptides-inhibiting-xanthomonas-citri-subsp-citri-causing-citrus-canker
#11
Jeahyuk Choi, Euiho Park, Se-Weon Lee, Jae-Wook Hyun, Kwang-Hyun Baek
Citrus canker disease decreases the fruit quality and yield significantly, furthermore, emerging of streptomycin-resistant pathogens threatens the citrus industry seriously because of a lack of proper control agents. Small synthetic antimicrobial peptides (AMPs) could be a promising alternative. Fourteen hexapeptides were selected by using positional scanning of synthetic peptide combinatorial libraries. Each hexapeptide showed different antimicrobial spectrum against Bacillus, Pseudomonas, Xanthomonas, and Candida species...
February 2017: Plant Pathology Journal
https://www.readbyqxmd.com/read/28165218/perfluoro-tert-butyl-homoserine-is-a-helix-promoting-highly-fluorinated-nmr-sensitive-aliphatic-amino-acid-detection-of-the-estrogen-receptor%C3%A2-coactivator-protein-protein-interaction-by-19-f-nmr
#12
Caitlin M Tressler, Neal J Zondlo
Highly fluorinated amino acids can stabilize proteins and complexes with proteins, via enhanced hydrophobicity, and provide novel methods for identification of specific molecular events in complex solutions, via selective detection by (19)F NMR and the absence of native (19)F signals in biological contexts. However, the potential applications of (19)F NMR in probing biological processes are limited both by the strong propensities of most highly fluorinated amino acids for the extended conformation and by the relatively modest sensitivity of NMR spectroscopy, which typically constrains measurements to mid-micromolar concentrations...
February 15, 2017: Biochemistry
https://www.readbyqxmd.com/read/28164758/angiotensin-peptides-as-at2-receptor-agonists
#13
Mathias Hallberg, Jonas Sävmarker, Anders Hallberg
In 2004, the first nonpeptide selective angiotensin II type 2 receptor (AT2R) agonist was reported. This nonpeptide (C21), which, exerts anti-inflammatory and antifibrotic actions in vivo, has been extensively explored and is currently in clinical trials. Subsequently, a large number of related drug-like AT2R agonists have been disclosed. Reviews that summarize known structure-activity relationships (SAR) of nonpeptide AT2R agonists have recently appeared in the literature; however, very few reviews discuss the role of angiotensin peptides as AT2R agonists...
February 3, 2017: Current Protein & Peptide Science
https://www.readbyqxmd.com/read/28146347/highly-constrained-bicyclic-scaffolds-for-the-discovery-of-protease-stable-peptides-via-mrna-display
#14
David E Hacker, Jan Hoinka, Emil S Iqbal, Teresa M Przytycka, Matthew C T Hartman
Highly constrained peptides such as the knotted peptide natural products are promising medicinal agents because of their impressive biostability and potent activity. Yet, libraries of highly constrained peptides are challenging to prepare. Here, we present a method which utilizes two robust, orthogonal chemical steps to create highly constrained bicyclic peptide libraries. This technology was optimized to be compatible with in vitro selections by mRNA display. We performed side-by-side monocyclic and bicyclic selections against a model protein (streptavidin)...
February 1, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28137809/a-short-double-stapled-peptide-inhibits-respiratory-syncytial-virus-entry-and-spreading
#15
Vanessa Gaillard, Marie Galloux, Dominique Garcin, Jean-François Eléouët, Ronan Le Goffic, Thibaut Larcher, Marie-Anne Rameix-Welti, Abdelhak Boukadiri, Julien Héritier, Jean-Manuel Segura, Elodie Baechler, Miriam Arrell, Geneviève Mottet-Osman, Origène Nyanguile
Synthetic peptides derived from the heptad repeat (HR) of fusion (F) proteins can be used as dominant negative inhibitors to inhibit the fusion mechanism of class I viral F proteins. Here, we have performed a stapled peptide scan across the HR2 domain of the RSV F protein with the aim to identify a minimal domain capable of disrupting the formation of the post fusion six helix bundle required for viral cell entry. Constraining the peptides with a single staple was not sufficient to inhibit RSV infection. However, the insertion of double staples led to the identification of novel short stapled peptides, which display nanomolar potency in HEp-2 cells, and are exceptionally robust to proteolytic degradation...
January 30, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28135077/mechanistic-understanding-of-lanthipeptide-biosynthetic-enzymes
#16
Lindsay M Repka, Jonathan R Chekan, Satish K Nair, Wilfred A van der Donk
Lanthipeptides are ribosomally synthesized and post-translationally modified peptides (RiPPs) that display a wide variety of biological activities, from antimicrobial to antiallodynic. Lanthipeptides that display antimicrobial activity are called lantibiotics. The post-translational modification reactions of lanthipeptides include dehydration of Ser and Thr residues to dehydroalanine and dehydrobutyrine, a transformation that is carried out in three unique ways in different classes of lanthipeptides. In a cyclization process, Cys residues then attack the dehydrated residues to generate the lanthionine and methyllanthionine thioether cross-linked amino acids from which lanthipeptides derive their name...
January 30, 2017: Chemical Reviews
https://www.readbyqxmd.com/read/28107435/peptide-targeted-by-human-antibodies-associated-with-hiv-vaccine-associated-protection-assumes-a-dynamic-%C3%AE-helical-structure
#17
Mohammed S Aiyegbo, Evgeny Shmelkov, Lorenzo Dominguez, Michael Goger, Shibani Battacharya, Allan C deCamp, Peter B Gilbert, Phillip W Berman, Timothy Cardozo
The only evidence of vaccine-induced protection from HIV acquisition in humans was obtained in the RV144 HIV vaccine clinical trial. One immune correlate of risk in RV144 was observed to be higher titers of vaccine-induced antibodies (Abs) reacting with a 23-mer non-glycosylated peptide with the same amino acid sequence as a segment in the second variable (V2) loop of the MN strain of HIV. We used NMR to analyze the dynamic 3D structure of this peptide. Distance restraints between spatially proximate inter-residue protons were calculated from NOE cross peak intensities and used to constrain a thorough search of all possible conformations of the peptide...
2017: PloS One
https://www.readbyqxmd.com/read/28105269/electrophilic-helical-peptides-that-bond-covalently-irreversibly-and-selectively-in-a-protein-protein-interaction-site
#18
Aline Dantas de Araujo, Junxian Lim, Andrew C Good, Renato T Skerlj, David P Fairlie
Protein-protein interactions mediate most physiological and disease processes. Helix-constrained peptides potently mimic or inhibit these interactions by making multiple contacts over large surface areas. However, despite high affinities, they typically have short lifetimes bound to the protein. Here we insert both a helix-inducing constraint and an adjacent electrophile into the native peptide ligand BIM to target the oncogenic protein Bcl2A1. The modified BIM peptide bonds covalently and irreversibly to one cysteine within the helix-binding groove of Bcl2A1, but not to two other exposed cysteines on its surface, and shows no covalent bonding to other Bcl2 proteins...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28059508/nonclassical-size-dependence-of-permeation-defines-bounds-for-passive-adsorption-of-large-drug-molecules
#19
Cameron R Pye, William M Hewitt, Joshua Schwochert, Terra D Haddad, Chad E Townsend, Lyns Etienne, Yongtong Lao, Chris Limberakis, Akihiro Furukawa, Alan M Mathiowetz, David A Price, Spiros Liras, R Scott Lokey
Macrocyclic peptides are considered large enough to inhibit "undruggable" targets, but the design of passively cell-permeable molecules in this space remains a challenge due to the poorly understood role of molecular size on passive membrane permeability. Using split-pool combinatorial synthesis, we constructed a library of cyclic, per-N-methlyated peptides spanning a wide range of calculated lipohilicities (0 < AlogP < 8) and molecular weights (∼800 Da < MW < ∼1200 Da). Analysis by the parallel artificial membrane permeability assay revealed a steep drop-off in apparent passive permeability with increasing size in stark disagreement with current permeation models...
January 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28054413/the-importance-of-being-aib-aggregation-and-self-assembly-studies-on-conformationally-constrained-oligopeptides
#20
REVIEW
Mariano Venanzi, Emanuela Gatto, Fernando Formaggio, Claudio Toniolo
The role of the conformationally constrained α-aminoisobutyric acid (Aib) residue in the aggregation and self-assembly properties of oligopeptides is discussed, critically reviewing our recent work in the field. In this connection, three significant case studies are presented: (i) aggregation propensity of Aib homo-oligopeptides of different length; (ii) perturbation of the conformational and aggregation properties of Ala-based pentapeptides by a single Aib versus Ala substitution; and (iii) build up of self-assembled monolayers formed by Aib homo-hexapeptide building blocks...
February 2017: Journal of Peptide Science: An Official Publication of the European Peptide Society
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