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Stapled peptides

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https://www.readbyqxmd.com/read/28073163/hydrocarbon-stapled-lipopeptides-exhibit-selective-antimicrobial-activity
#1
Zachary B Jenner, Christopher M Crittenden, Martín Gonzalez, Jennifer S Brodbelt, Kerry A Bruns
Antimicrobial peptides (AMPs) occur widely in nature and have been studied for their therapeutic potential. AMPs are of interest due to the large number of possible chemical structural combinations using natural and unnatural amino acids, with varying effects on their biological activities. Using physicochemical properties from known naturally occurring amphipathic cationic AMPs, several hydrocarbon-stapled lipopeptides (HSLPs) were designed, synthesized, and tested for antimicrobial properties. Peptides were chemically modified by N-terminal acylation, C-terminal amidation, and some were hydrocarbon stapled by intramolecular olefin metathesis...
January 10, 2017: Biopolymers
https://www.readbyqxmd.com/read/28048940/towards-understanding-the-molecular-recognition-of-albumin-by-p53-activating-stapled-peptide-atsp-7041
#2
Garima Tiwari, Chandra S Verma
Reactivation of tumor suppressing activity of p53 protein by targeting its negative regulator MDM2/MDMX has been pursued as a potential anticancer strategy. A promising dual inhibitor of MDM2/MDMX that has been developed and is currently in clinical trials is the stapled-peptide ATSP-7041. The activity of this molecule is reported to be modulated in the presence of serum. Albumin is the most abundant protein in serum and is known to bind reversibly to several molecules. To study this interaction, we develop a protocol combining molecular modeling, docking and simulations...
January 3, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28042965/molecular-simulations-identify-binding-poses-and-approximate-affinities-of-stapled-%C3%AE-%C3%AF-%C3%AF-helical-peptides-to-mdm2-and-mdmx
#3
Joseph A Morrone, Alberto Perez, Qiaolin Deng, Sookhee Nicole Ha, M Katharine Holloway, Tom K Sawyer, Bradley S Sherborne, Frank K Brown, Ken A Dill
Traditionally, computing the binding affinities of proteins to even relatively small and rigid ligands by free-energy methods has been challenging due to large computational costs and significant errors. Here, we apply a new molecular simulation acceleration method called MELD (Modeling by Employing Limited Data) to study the binding of stapled helical peptides to the MDM2 and MDMX proteins. We employ free energy based molecular dynamics simulations (MELD-MD) to identify binding poses and calculate binding affinities...
January 2, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/27900857/stapled-peptides-by-late-stage-c-sp-3-h-activation
#4
Anaïs F M Noisier, Jesús García, Ioana A Ionuţ, Fernando Albericio
Despite the importance of stapled peptides for drug discovery, only few practical processes to prepare cross-linked peptides have been described; thus the structural diversity of available staple motifs is currently limited. At the same time, C-H activation has emerged as an efficient approach to functionalize complex molecules. Although there are many reports on the C-H functionalization of amino acids, examples of post-synthetic peptide C-H modification are rare and comprise almost only C(sp(2) )-H activation...
January 2, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/27819377/downsizing-the-bad-bh3-peptide-to-small-constrained-%C3%AE-helices-with-improved-ligand-efficiency
#5
Nicholas E Shepherd, Rosemary S Harrison, Gloria Ruiz-Gomez, Giovanni Abbenante, Jody M Mason, David P Fairlie
Bcl2 Homology (BH) proteins can either trigger or prevent programmed cell death or apoptosis. Deregulation of the BH protein family network leads to evasion of apoptosis, uncontrolled proliferation and is a hallmark of cancer. Inhibition of pro-survival BH proteins is a promising chemotherapeutic strategy for certain cancers. We have examined whether helix-constrained peptides based on the BAD BH3 domain (residues 103-127) can be downsized to much smaller more drug-like peptides. We report the preparation, structural characterisation, in vitro Bcl-xL inhibition and leukemic T-cell killing ability of 45 linear, mono-, bi- and tricyclic helical peptidomimetics between 8- and 19-residues in length...
November 7, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27775325/a-tpx2-proteomimetic-has-enhanced-affinity-for-aurora-a-due-to-hydrocarbon-stapling-of-a-helix
#6
Yana K Rennie, Patrick J McIntyre, Tito Akindele, Richard Bayliss, Andrew G Jamieson
Inhibition of protein kinases using ATP-competitive compounds is an important strategy in drug discovery. In contrast, the allosteric regulation of kinases through the disruption of protein-protein interactions has not been widely adopted, despite the potential for selective targeting. Aurora-A kinase regulates mitotic entry and mitotic spindle assembly and is a promising target for anticancer therapy. The microtubule-associated protein TPX2 activates Aurora-A through binding to two sites. Aurora-A recognition is mediated by two motifs within the first 43 residues of TPX2, connected by a flexible linker...
December 16, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27722656/the-key-position-influence-of-staple-location-on-constrained-peptide-conformation-and-binding
#7
Kelly L Keeling, Okki Cho, Denis B Scanlon, Grant W Booker, Andrew D Abell, Kate L Wegener
Constrained α-helical peptides are showing potential as biological probes and therapeutic agents that target protein-protein interactions. However, the factors that determine the optimal constraint locations are still largely unknown. Using the β-integrin/talin protein interaction as a model system, we examine the effect of constraint location on helical conformation, as well as binding affinity, using circular dichroism and NMR spectroscopy. Stapling increased the overall helical content of each integrin-based peptide tested...
October 18, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27721413/mechanistic-validation-of-a-clinical-lead-stapled-peptide-that-reactivates-p53-by-dual-hdm2-and-hdmx-targeting
#8
F Wachter, A M Morgan, M Godes, R Mourtada, G H Bird, L D Walensky
Hydrocarbon-stapled peptides that display key residues of the p53 transactivation domain have emerged as bona fide clinical candidates for reactivating the tumor suppression function of p53 in cancer by dual targeting of the negative regulators HDM2 and HDMX. A recent study questioned the mechanistic specificity of such stapled peptides based on interrogating their capacity to disrupt p53/HDM2 and p53/HDMX complexes in living cells using a new recombinase enhanced bimolecular luciferase complementation platform (ReBiL)...
October 10, 2016: Oncogene
https://www.readbyqxmd.com/read/27718641/discovery-and-optimization-of-peptide-macrocycles
#9
Andrew M White, David J Craik
Macrocyclic peptides are generally more resistant to proteolysis and often have higher potency than linear peptides and so they are excellent leads in drug design. Their study is significant because they offer potential as a new generation of drugs that are potent and specific, and thus might have fewer side effects than traditional small molecule drugs. Areas covered: This article covers macrocyclic drug leads based on nature-derived cyclic peptides as well as synthetic cyclic peptides and close derivatives...
October 10, 2016: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/27662249/a-new-staple-peptide-targeted-covalent-inhibitors
#10
Joel D Leverson
In this issue of Cell Chemical Biology, Huhn et al. (2016) unveil a clever strategy for selectively and irreversibly inhibiting an anti-apoptotic protein, BFL-1. The authors describe stapled peptides bearing carefully placed electrophiles that target a unique cysteine residue in BFL-1 via covalent modification, thus representing an extension of the stapled peptide concept into the covalent inhibitor space.
September 22, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27649052/stapled-peptides-how-to-be-quick-on-the-uptake
#11
Joshua A Kritzer
No abstract text is available yet for this article.
September 20, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27648609/rice-bran-protein-as-a-potent-source-of-antimelanogenic-peptides-with-tyrosinase-inhibitory-activity
#12
Akihito Ochiai, Seiya Tanaka, Takaaki Tanaka, Masayuki Taniguchi
Rice (Oryza sativa) is consumed as a staple food globally, and rice bran, the byproduct, is an unused biomass that is ultimately discarded as waste. Thus, in the present study, a technique for producing tyrosinase inhibitory peptides from rice bran protein (RBP) was developed. Simultaneous treatment of RBP with chymotrypsin and trypsin produced numerous peptides. Subsequently, six tyrosinase inhibitory peptides were isolated from the hydrolysate fractions in a multistep purification protocol, and their amino acid sequences were determined...
September 20, 2016: Journal of Natural Products
https://www.readbyqxmd.com/read/27643505/challenges-in-targeting-a-basic-helix-loop-helix-transcription-factor-with-hydrocarbon-stapled-peptides
#13
Amanda L Edwards, Dimphna H Meijer, Rachel M Guerra, Remco J Molenaar, John A Alberta, Federico Bernal, Gregory H Bird, Charles D Stiles, Loren D Walensky
Basic helix-loop-helix (bHLH) transcription factors play critical roles in organism development and disease by regulating cell proliferation and differentiation. Transcriptional activity, whether by bHLH homo- or heterodimerization, is dependent on protein-protein and protein-DNA interactions mediated by α-helices. Thus, α-helical decoys have been proposed as potential targeted therapies for pathologic bHLH transcription. Here, we developed a library of stabilized α-helices of OLIG2 (SAH-OLIG2) to test the capacity of hydrocarbon-stapled peptides to disrupt OLIG2 homodimerization, which drives the development and chemoresistance of glioblastoma multiforme, one of the deadliest forms of human brain cancer...
November 18, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27623032/flexible-vs-rigid-epitope-conformations-for-diagnostic-and-vaccine-oriented-applications-novel-insights-from-the-burkholderia-pseudomallei-bpsl2765-pal3-epitope
#14
Alessandro Gori, Claudio Peri, Giacomo Quilici, Arnone Nithichanon, Davide Gaudesi, Renato Longhi, Louise Gourlay, Martino Bolognesi, Ganjana Lertmemongkolchai, Giovanna Musco, Giorgio Colombo
Peptides seldom retain stable conformations if separated from their native protein structure. In an immunological context, this potentially affects the development of selective peptide-based bioprobes and, from a vaccine perspective, poses inherent limits in the elicitation of cross-reactive antibodies by candidate epitopes. Here, a 1,4-disubstituted-1,2,3-triazole-mediated stapling strategy was used to stabilize the native α-helical fold of the Pal3 peptidic epitope from the protein antigen PalBp (BPSL2765) from Burkholderia pseudomallei, the etiological agent of melioidosis...
March 11, 2016: ACS Infectious Diseases
https://www.readbyqxmd.com/read/27617850/selective-covalent-targeting-of-anti-apoptotic-bfl-1-by-cysteine-reactive-stapled-peptide-inhibitors
#15
Annissa J Huhn, Rachel M Guerra, Edward P Harvey, Gregory H Bird, Loren D Walensky
Anti-apoptotic BCL-2 family proteins block cell death by trapping the critical α-helical BH3 domains of pro-apoptotic members in a surface groove. Cancer cells hijack this survival mechanism by overexpressing a spectrum of anti-apoptotic members, mounting formidable apoptotic blockades that resist chemotherapeutic treatment. Drugging the BH3-binding pockets of anti-apoptotic proteins has become a highest-priority goal, fueled by the clinical success of ABT-199, a selective BCL-2 inhibitor, in reactivating apoptosis in BCL-2-dependent cancers...
September 22, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27580024/therapeutic-design-of-peptide-modulators-of-protein-protein-interactions-in-membranes
#16
Tracy A Stone, Charles M Deber
Membrane proteins play the central roles in a variety of cellular processes, ranging from nutrient uptake and signalling, to cell-cell communication. Their biological functions are directly related to how they fold and assemble; defects often lead to disease. Protein-protein interactions (PPIs) within the membrane are therefore of great interest as therapeutic targets. Here we review the progress in the application of membrane-insertable peptides for the disruption or stabilization of membrane-based PPIs. We describe the design and preparation of transmembrane peptide mimics; and of several categories of peptidomimetics used for study, including d-enantiomers, non-natural amino acids, peptoids, and β-peptides...
August 28, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27574543/peptide-translocation-through-the-plasma-membrane-of-human-cells-can-oxidative-stress-be-exploited-to-gain-better-intracellular-access
#17
Ting-Yi Wang, Jean-Philippe Pellois
Cell-penetrating peptides (CPPs) enter cells primarily by escaping from endosomal compartments or by directly translocating across the plasma membrane. Due to their capability of permeating into the cytosolic space of the cell, CPPs are utilized for the delivery of cell-impermeable molecules. However, the fundamental mechanisms and parameters associated with the penetration of CPPs and their cargos through the lipid bilayer have not been fully determined. This in turn has hampered their usage in biotechnological or therapeutic applications...
July 2016: Communicative & Integrative Biology
https://www.readbyqxmd.com/read/27547919/biophysical-determinants-for-cellular-uptake-of-hydrocarbon-stapled-peptide-helices
#18
Gregory H Bird, Emanuele Mazzola, Kwadwo Opoku-Nsiah, Margaret A Lammert, Marina Godes, Donna S Neuberg, Loren D Walensky
Hydrocarbon-stapled peptides are a class of bioactive alpha-helical ligands developed to dissect and target protein interactions. While there is consensus that stapled peptides can be effective chemical tools for investigating protein regulation, their broader utility for therapeutic modulation of intracellular interactions remains an active area of study. In particular, the design principles for generating cell-permeable stapled peptides are empiric, yet consistent intracellular access is essential to in vivo application...
October 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27532490/benzene-probes-in-molecular-dynamics-simulations-reveal-novel-binding-sites-for-ligand-design
#19
Yaw Sing Tan, Judith Reeks, Christopher J Brown, Dawn Thean, Fernando Jose Ferrer Gago, Tsz Ying Yuen, Eunice Tze Leng Goh, Xue Er Cheryl Lee, Claire E Jennings, Thomas L Joseph, Rajamani Lakshminarayanan, David P Lane, Martin E M Noble, Chandra S Verma
Protein flexibility poses a major challenge in binding site identification. Several computational pocket detection methods that utilize small-molecule probes in molecular dynamics (MD) simulations have been developed to address this issue. Although they have proven hugely successful at reproducing experimental structural data, their ability to predict new binding sites that are yet to be identified and characterized has not been demonstrated. Here, we report the use of benzenes as probe molecules in ligand-mapping MD (LMMD) simulations to predict the existence of two novel binding sites on the surface of the oncoprotein MDM2...
September 1, 2016: Journal of Physical Chemistry Letters
https://www.readbyqxmd.com/read/27527801/two-novel-antimicrobial-defensins-from-rice-identified-by-gene-coexpression-network-analyses
#20
Supaluk Tantong, Onanong Pringsulaka, Kamonwan Weerawanich, Arthitaya Meeprasert, Thanyada Rungrotmongkol, Rakrudee Sarnthima, Sittiruk Roytrakul, Supaart Sirikantaramas
Defensins form an antimicrobial peptides (AMP) family, and have been widely studied in various plants because of their considerable inhibitory functions. However, their roles in rice (Oryza sativa L.) have not been characterized, even though rice is one of the most important staple crops that is susceptible to damaging infections. Additionally, a previous study identified 598 rice genes encoding cysteine-rich peptides, suggesting there are several uncharacterized AMPs in rice. We performed in silico gene expression and coexpression network analyses of all genes encoding defensin and defensin-like peptides, and determined that OsDEF7 and OsDEF8 are coexpressed with pathogen-responsive genes...
October 2016: Peptides
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