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Peptide mimics

Jean-Michel Paumier, Nathalie A Py, Laura García-González, Anne Bernard, Delphine Stephan, Laurence Louis, Frédéric Checler, Michel Khrestchatisky, Kévin Baranger, Santiago Rivera
We previously demonstrated that membrane type 1 (MT1) matrix metalloproteinase (MMP) was up-regulated in the hippocampus of the model of transgenic mice bearing 5 familial mutations on human amyloid precursor protein (APP) and presenilin 1 of Alzheimer disease (AD), and that the proteinase increased the levels of amyloid β peptide (Aβ) and its APP C-terminal fragment of 99 aa in a heterologous cell system. Here we provide further evidence that MT1-MMP interacts with APP and promotes amyloidogenesis in a proteolytic-dependent manner in Swedish APP-expressing HEK293 cells (HEKswe)...
October 17, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Uris Ros, Gustavo P B Carretero, Joana Paulino, Edson Crusca, Fabiola Pazos, Eduardo M Cilli, Maria E Lanio, Shirley Schreier, Carlos Alvarez
Sticholysin I and II (Sts: St I and St II) are proteins of biomedical interest that form pores upon the insertion of their N-terminus in the plasma membrane. Peptides spanning the N-terminal residues of StI (StI1-31 ) or StII (StII1-30 ) can mimic the permeabilizing ability of these toxins, emerging as candidates to rationalize their potential biomedical applications. These peptides have different activities that correlate with their hydrophobicity. However, it is not clear how this property contributes to peptide folding in solution or upon binding to membranes...
October 13, 2018: Biochimie
Chino C Cabalteja, Daniel S Mihalko, William Seth Horne
Disulfide-rich peptides have found widespread use in the development of bioactive agents; however, low proteolytic stability and difficulty exerting synthetic control over chain topology present barriers to applications in some systems. Here, we report a method that enables creation of artificial backbone ("foldamer") mimics of compact, disulfide-rich tertiary folds. Systematic replacement of a subset of natural α-residues with various artificial building blocks in the context of a computationally designed prototype sequence leads to "heterogeneous backbone" variants that undergo clean oxidative folding, adopt tertiary structures indistinguishable from the prototype, and enjoy proteolytic protection beyond that inherent to the topologically constrained scaffold...
October 16, 2018: Chembiochem: a European Journal of Chemical Biology
Katarina D Kovacevic, James C Gilbert, Bernd Jilma
Aptamers are synthetic molecules structured as single-stranded DNA or RNA oligonucleotides that can be designed to mimic the functional properties of monoclonal antibodies. They bind to the target molecules (typically soluble or cell-bound proteins) with high affinity (with picomolar to low nanomolar range) and specificity, and therefore can be an alternative to therapeutic antibodies or peptide ligands. This paper reviews published data regarding pharmacokinetics, pharmacodynamics and safety of aptamers from preclinical and clinical studies...
October 12, 2018: Advanced Drug Delivery Reviews
Kornelia J Skowron, Thomas E Speltz, Terry W Moore
Given the ubiquity of the ⍺-helix in the proteome, there has been much research in developing mimics of ⍺-helices, and most of this study has been toward developing protein-protein interaction inhibitors. A common strategy for mimicking ⍺-helices has been through the use of constrained, helical peptides. The addition of a constraint typically provides for conformational and proteolytic stability and, in some cases, cell permeability. Some of the most well-known strategies included are lactam formation and hydrocarbon "stapling...
October 11, 2018: Medicinal Research Reviews
Vasilios G Athyros, Niki Katsiki, Aikaterini Dimakopoulou, Dimitrios Patoulias, Sofia Alataki, Michael Doumas
BACKGROUND: Drugs mimicking natural beneficial mutations, including that for familial hypercholesterolemia (FH), might represent the future of hypolipidemic drug treatment. OBJECTIVE: The aim of this review is to review the properties and the effects of these drugs, which are either already commercially available or are in the process to be approved for the treatment of dyslipidemia. RESULTS: More than a decade ago, it was accidentally discovered that proprotein convertase subtilisin/kexin type 9 (PCSK9) loss-of-function mutations resulted in marked lifelong reduction of LDL-C and the incidence of cardiovascular disease (CVD)...
October 8, 2018: Current Pharmaceutical Design
Annalisa Ferino, Giulia Miglietta, Raffaella Picco, Stefan Vogel, Jesper Wengel, Luigi E Xodo
Datasets reporting microRNA expression profiles in normal and cancer cells show that miR-216b is aberrantly downregulated in pancreatic ductal adenocarcinoma (PDAC). We found that KRAS, whose mutant G12D allele drives the pathogenesis of PDAC, is a target of miR-216b. To suppress oncogenic KRAS in PDAC cells, we designed single-stranded (ss) miR-216b mimics with unlocked nucleic acid (UNA) modifications to enhance their nuclease resistance. We prepared variants of ss-miR-216b mimics with and without a 5' phosphate group...
October 11, 2018: RNA Biology
Raquel Planas, Radleigh Santos, Paula Tomas-Ojer, Carolina Cruciani, Andreas Lutterotti, Wolfgang Faigle, Nicole Schaeren-Wiemers, Carmen Espejo, Herena Eixarch, Clemencia Pinilla, Roland Martin, Mireia Sospedra
Multiple sclerosis is an immune-mediated autoimmune disease of the central nervous system that develops in genetically susceptible individuals and likely requires environmental triggers. The autoantigens and molecular mimics triggering the autoimmune response in multiple sclerosis remain incompletely understood. By using a brain-infiltrating CD4+ T cell clone that is clonally expanded in multiple sclerosis brain lesions and a systematic approach for the identification of its target antigens, positional scanning peptide libraries in combination with biometrical analysis, we have identified guanosine diphosphate (GDP)-l-fucose synthase as an autoantigen that is recognized by cerebrospinal fluid-infiltrating CD4+ T cells from HLA-DRB3*-positive patients...
October 10, 2018: Science Translational Medicine
Antoine Douchez, Azade Geranurimi, William D Lubell
γ,δ-Unsaturated ketones, so-called homoallylic ketones, have served as versatile building blocks for the synthesis of a variety of heterocycles, carbocycles, natural products, and reactive intermediates. Procured by a variety of processes, including conjugate addition of vinyl organometallic reagents to unsaturated ketones, allylation of silyl enol ethers, and rearrangements, homoallylic ketones are often synthesized by step-intensive methods. The cascade addition of 2 equiv of vinyl Grignard reagent to a carboxylate was reported by the Lubell laboratory in 2003 to give effective access to homoallylic ketones from a variety of aromatic, aliphatic, and α-amino methyl esters...
October 5, 2018: Accounts of Chemical Research
Gautam Srivastava, Adi Moseri, Naama Kessler, Boris Arshava, Fred Naider, Jacob Anglister
Infection by HIV-1 requires protein-protein interactions involving gp120, CD4 and CCR5. We have previously demonstrated that the transferred nuclear Overhauser effect, TRNOE, in combination with asymmetric deuteration of a protein and a peptide ligand can be used to detect intermolecular interactions in large protein complexes with molecular weights up to ~100 kDa. Here, using this approach, we reveal interactions between tyrosine residues of a 27-residue peptide corresponding to the N-terminal segment of the CCR5 chemokine receptor, and a dimeric extended core YU 2 gp120 envelope protein of HIV-1 complexed with a CD4-mimic miniprotein...
October 5, 2018: FEBS Journal
Shingo Shimodaira, Toshiki Takei, Hironobu Hojo, Michio Iwaoka
Selenocysteine-containing cyclic 8-mer peptides, which were designed to mimic the plausible catalytic tetrad of glutathione peroxidase, were successfully synthesized in one pot via tandem N-to-S acyl migration of N-alkylcysteine (NAC)-containing selenopeptides and intramolecular selenocysteine-mediated native chemical ligation (Sec-NCL) of the generated thioesters.
October 25, 2018: Chemical Communications: Chem Comm
Gema Dura, Helen Waller, Piergiorgio Gentile, Jeremy H Lakey, David A Fulton
Capsular antigen fraction 1 (Caf1) is a robust polymeric protein forming a protective layer around the bacterium Yersinia pestis. Occurring as ≈1 μm polymeric fibers, it shares its immunoglobulin-like fold with the majority of mammalian extracellular proteins such as fibronectin and this structural similarity suggests that this unusual polymer could form useful mimics of the extracellular matrix. Driven by the pressing need for reliable animal-free 3D cell culture environments, we showed previously that recombinant Caf1 produced in Escherichia coli can be engineered to include bioactive peptides, which influence cell behavior...
December 1, 2018: Materials Science & Engineering. C, Materials for Biological Applications
Rafael Gomes Von Borowski, Simone Cristina Baggio Gnoatto, Alexandre José Macedo, Reynald Gillet
Pathogenic biofilms are a global health care concern, as they can cause extensive antibiotic resistance, morbidity, mortality, and thereby substantial economic loss. Scientific efforts have been made over the past few decades, but so far there is no effective treatment targeting the bacteria in biofilms. Antimicrobial peptidomimetics have been proposed as promising potential anti-biofilm agents. Indeed, these structurally enhanced molecules can mimic the action of peptides but are not susceptible to proteolysis or immunogenicity, the characteristic limitations of natural peptides...
2018: Frontiers in Microbiology
Hongqing Guo, Trevor M Nolan, Gaoyuan Song, Sanzhen Liu, Zhouli Xie, Jiani Chen, Patrick S Schnable, Justin W Walley, Yanhai Yin
Bacterial pathogens use effectors and phytotoxins to facilitate infection of host plants. Coronatine (COR) is one of the phytotoxins produced in bacterial pathogens, such as Pseudomonas syringae pv. tomato DC3000 (pst DC3000). COR structurally and functionally mimics the active form of the plant hormone jasmonic acid (JA), JA-isoleucine (JA-Ile), and can hijack the host JA-signaling pathway to achieve host disease susceptibility [1]. COR utilizes the transcription factor MYC2, a master regulator of JA signaling, to activate NAC transcription factors, which functions to inhibit accumulation of salicylic acid (SA) and thus compromise host immunity [2]...
September 14, 2018: Current Biology: CB
Carlo O Martins, Cecillia Lezcano, San S Yi, Heather J Landau, Jessica R Chapman, Ahmet Dogan
No abstract text is available yet for this article.
September 27, 2018: Haematologica
Mao Ding, Yang Shen, Ping Wang, Zhaohong Xie, Shunliang Xu, ZhengYu Zhu, Yun Wang, Yongtao Lyu, Dewei Wang, Linlin Xu, JianZhong Bi, Hui Yang
Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by excessive accumulation of the amyloid-β peptide (Aβ) in the brain, which has been considered to mediate the neuroinflammation process. Microglial activation is the main component of neuroimmunoregulation. In recent years, exosomes isolated from human umbilical cord mesenchymal stem cells (hucMSC-exosomes) have been demonstrated to mimic the therapeutic effects of hucMSCs in many inflammation-related diseases. In this study, exosomes from the supernatant of hucMSCs were injected into AD mouse models...
September 26, 2018: Neurochemical Research
Hongjun Yu, Tania J Lupoli, Amanda Kovach, Xing Meng, Gongpu Zhao, Carl F Nathan, Huilin Li
The protein disaggregase ClpB hexamer is conserved across evolution and has two AAA+-type nucleotide-binding domains, NBD1 and NBD2, in each protomer. In M. tuberculosis ( Mtb ), ClpB facilitates asymmetric distribution of protein aggregates during cell division to help the pathogen survive and persist within the host, but a mechanistic understanding has been lacking. Here we report cryo-EM structures at 3.8- to 3.9-Å resolution of Mtb ClpB bound to a model substrate, casein, in the presence of the weakly hydrolyzable ATP mimic adenosine 5'-[γ-thio]triphosphate...
October 9, 2018: Proceedings of the National Academy of Sciences of the United States of America
Mitsuhiro Hirai, Satoshi Ajito, Shouki Sato, Noboru Ohta, Noriyuki Igarashi, Nobutaka Shimizu
This study focuses on the interaction of human amyloid β-peptide (Aβ) with a lipid-raft model membrane under macromolecular crowding conditions that mimic the intracellular environment. Aβ is central to the development of Alzheimer's disease (AD) and has been studied extensively to determine the molecular mechanisms of Aβ-induced cellular dysfunctions underlying the pathogenesis of AD. According to evidence from spectroscopic studies, ganglioside clusters are key to the fibrillization process of Aβ. Gangliosides are a major component of glycosphingolipids and are acidic lipids of the central nervous system known to form so-called lipid rafts...
September 26, 2018: Journal of Physical Chemistry. B
Zhenhuan Zhao, Jiling Ren, Chao Dai, Carol C Kannapell, Hongyang Wang, Felicia Gaskin, Shu Man Fu
OBJECTIVES: The generation of systemic lupus erythematosus (SLE)-related autoantibodies have been shown to be T cell dependent and antigen driven with HLA-DR restriction. In this study, the initiating antigen(s) and the mechanism of autoantibody diversification were investigated. METHODS: T cell epitopes (T-epitopes) of SmD1 (SmD) were mapped by T-T hybridomas generated from DR3+ AE0 mice immunised with SmD and with SmD overlapping peptides. TCRs from the reactive hybridomas were sequenced...
September 25, 2018: Annals of the Rheumatic Diseases
Tania Ismail, Mathumai Kanapathipillai
Tau protein aggregation is believed to be one of the key drivers of Alzheimer's disease. The two hexapeptide amino acid sequences 306 VQIVYK311 and 275 VQIINK280 of the tau protein are responsible for aggregation, and subsequent functional loss leading to Alzheimer's progression. Hence, it is important to understand the factors that promote the self-aggregation of this tau peptide fragments. Cellular microenvironmental polyanions are known to play a major role in tau protein aggregation and loss of function...
September 24, 2018: Journal of Peptide Science: An Official Publication of the European Peptide Society
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