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cyclization peptides

Matthias Bochtler, Danuta Mizgalska, Florian Veillard, Magdalena L Nowak, John Houston, Paul Veith, Eric C Reynolds, Jan Potempa
Bacteroidetes feature prominently in the human microbiome, as major colonizers of the gut and clinically relevant pathogens elsewhere. Here, we reveal a new Bacteroidetes specific feature in the otherwise widely conserved Sec/SPI (Sec translocase/signal peptidase I) pathway. In Bacteroidetes , but not the entire FCB group or related phyla, signal peptide cleavage exposes N-terminal glutamine residues in most SPI substrates. Reanalysis of published mass spectrometry data for five Bacteroidetes species shows that the newly exposed glutamines are cyclized to pyroglutamate (also termed 5-oxoproline) residues...
2018: Frontiers in Microbiology
Hui Ye
Antimicrobial peptides are derived from the viral fusion domain of influenza virus hemagglutinin based on rational analysis of the intermolecular interaction between peptides and bacterial outer membrane. It is revealed that the isolated viral fusion domain is a negatively charged peptide HAfp1-23 that cannot effectively interact with the anionic membrane. Conversion of the native HAfp1-23 to a positively charged peptide HAfp1-23 _KK by E11K/D19K mutation can promote the peptide-membrane interaction substantially; this confers to the peptide a moderate antibacterial potency against antibiotic-resistant bacterial strains...
March 2018: Journal of Peptide Science: An Official Publication of the European Peptide Society
Mahboubeh Kheirabadi, Gardner S Creech, Jennifer X Qiao, David S Nirschl, David K Leahy, Kenneth M Boy, Percy H Carter, Martin D Eastgate
Macrocyclic peptides containing N-alkylated amino acids have emerged as a promising therapeutic modality, capable of modulating protein-protein interactions and intracellular delivery of hydrophilic payloads. While multi-channel automated Solid Phase Peptide Synthesis (SPPS) is a practical approach for peptide synthesis, the requirement for slow and inefficient chromatographic purification of the product peptides is a significant limitation to exploring these novel compounds. Herein, we invent a "catch-release" strategy for the non-chromatographic purification of macrocyclic peptides...
March 14, 2018: Journal of Organic Chemistry
Kenneth D Clevenger, Rosa Ye, Jin Woo Bok, Paul M Thomas, Md Nurul Islam, Galen P Miley, Matthew Robey, Cynthia Chen, KaHoua Yang, Michael Swyers, Edward Wu, Peng Gao, Chengcang Wu, Nancy P Keller, Neil L Kelleher
The benzodiazepine benzomalvin A/D is a fungal-derived specialized metabolite and inhibitor of the substance P receptor NK1, biosynthesized by a three-gene non-ribosomal peptide synthetase cluster. Here, we utilize <u>f</u>ungal <u>a</u>rtificial <u>c</u>hromosomes with <u>m</u>etabolomic <u>s</u>coring (FAC-MS) to carry out molecular genetic pathway dissection and targeted metabolomics analysis to assign the in vivo role of each domain in the benzomalvin biosynthetic pathway...
March 13, 2018: Biochemistry
Daniel P Teufel, Gavin Bennett, Helen Harrison, Katerine van Rietschoten, Silvia Pavan, Catherine Stace, François Le Floch, Tine Van Bergen, Elke Vermassen, Philippe Barbeaux, Tjing-Tjing Hu, Jean H M Feyen, Marc Vanhove
Plasma kallikrein, a member of the kallikrein-kinin system, catalyzes the release of the bioactive peptide bradykinin, which induces inflammation, vasodilation, vessel permeability and pain. Preclinical evidence implicates the activity of plasma kallikrein in diabetic retinopathy, which is a leading cause of visual loss in patients suffering from diabetes mellitus. Employing a technology based on phage-display combined with chemical cyclization, we have identified highly selective bicyclic peptide inhibitors with nano- and pico-molar potencies towards plasma kallikrein...
March 8, 2018: Journal of Medicinal Chemistry
Rajiv Dahiya, Sunil Singh
Synthesis of a proline-rich cyclic hexapeptide - diandrine A [VI] was accomplished by coupling of tetrapeptide unit Boc-Gly-Pro-Trp-Pro-OH with dipeptide unit Tyr-Phe-OMe followed by cyclization of linear peptide unit [V] under alkaline condition. Structure of newly synthesized cyclopolypeptide was elucidated by means of spectral techniques including FTIR, 'H NMR, "C NMR, MS analyses. VI was subjected to pharmacological screening and found to exhibit good antifungal activity against dermatophytes. Further, VI possessed potent antihelmintic activity against earthworms M...
May 2017: Acta Poloniae Pharmaceutica
Marta Ruiz-Santaquiteria, Sonia de Castro, Miguel A Toro, Héctor de Lucio, Kilian Jesús Gutiérrez, Pedro A Sánchez-Murcia, María Ángeles Jiménez, Federico Gago, Antonio Jiménez-Ruiz, María-José Camarasa, Sonsoles Velázquez
Trypanothione reductase (TryR) is a well-established target in the search for novel antitrypanosomal and antileishmanial agents. We have previously identified linear and lactam-bridged 13-residue peptides derived from an α-helical region making up part of the dimeric interface of Leishmania infantum TryR (Li-TryR) which prevent trypanothione reduction by disrupting enzyme dimerization. We now show that i,i + 4 side-chain cross-linking with an all-hydrocarbon staple stabilizes the helical structure of these peptides and significantly improves their resistance to protease cleavage relative to previous linear and cyclic lactam analogues...
February 24, 2018: European Journal of Medicinal Chemistry
Xiangxiang Shi, Jun Zheng, Tingting Yan
Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and young children. Here, the RSV fusion (F) glycoprotein epitope FFL was redesigned based on its complex crystal structure with motavizumab, an mAb drug in development for the prevention of RSV infections, aiming to obtain therapeutic peptide vaccines with high affinity to induce RSV-specific neutralizing antibodies. Computational modeling and analysis found that only a small region covering the helix-turn-helix (HTH) motif of FFL can directly interact with motavizumab and confer stability and specificity to the complex system, while the rest of the epitope primarily serves as a structural scaffold that stabilizes the HTH conformation of motavizumab-binding site...
March 2, 2018: Journal of Molecular Modeling
Jinhua Fu, Hong Yang, Jing Wang
Peptides with helical hairpin conformation have been found to possess potent membrane activity and can be exploited as the structural scaffold of antibacterial peptides (ABPs). Here, we attempted to computationally design membrane-active ABPs based on the helical hairpin motif of respiratory syncytial virus (RSV) glycoprotein epitope. Dynamics simulations revealed that the epitope peptide Rfe (net charge = -1) cannot effectively interact with and permeabilize bacterial membrane due to the electrostatic repulsion between the negatively charged peptide and anionic membrane surface...
February 21, 2018: Computational Biology and Chemistry
Theetha L Pavankumar
Inteins are self-splicing polypeptides with an ability to excise themselves from flanking host protein regions with remarkable precision; in the process, they ligate flanked host protein fragments. Inteins are distributed sporadically across all three domains of life (bacteria, archaea, and unicellular eukaryotes). However, their apparent localized distribution in DNA replication, repair, and recombination proteins (the 3Rs), particularly in bacteria and archaea, is enigmatic. Our understanding of the localized distribution of inteins in the 3Rs, and their possible regulatory role in such distribution, is still only partial...
February 28, 2018: Microorganisms
Juliana Cotabarren, Mariana Edith Tellechea, Sebastián Martín Tanco, Julia Lorenzo, Javier Garcia-Pardo, Francesc Xavier Avilés, Walter David Obregón
Cystine-knot miniproteins (CKMPs) are an intriguing group of cysteine-rich molecules that combine the characteristics of proteins and peptides. Typically, CKMPs are fewer than 50 residues in length and share a characteristic knotted scaffold characterized by the presence of three intramolecular disulfide bonds that form the singular knotted structure. The knot scaffold confers on these proteins remarkable chemical, thermal, and proteolytic stability. Recently, CKMPs have emerged as a novel class of natural molecules with interesting pharmacological properties...
February 28, 2018: International Journal of Molecular Sciences
Ryota Kirikoshi, Noriyoshi Manabe, Ohgi Takahashi
Aspartic acid (Asp) residues in proteins and peptides are prone to the non-enzymatic reactions that give biologically uncommon l-β-Asp, d-Asp, and d-β-Asp residues via the cyclic succinimide intermediate (aminosuccinyl residue, Suc). These abnormal Asp residues are known to have relevance to aging and pathologies. Despite being non-enzymatic, the Suc formation is thought to require a catalyst under physiological conditions. In this study, we computationally investigated the mechanism of the Suc formation from Asp residues that were catalyzed by the dihydrogen phosphate ion, H₂PO₄- ...
February 24, 2018: International Journal of Molecular Sciences
Kien Tran, Alexandre Murza, Xavier Sainsily, David Coquerel, Jérôme Côté, Karine Belleville, Lounès Haroune, Jean-Michel Longpré, Robert Dumaine, Dany Salvail, Olivier Lesur, Mannix Auger-Messier, Philippe Sarret, Éric Marsault
The apelin receptor generates increasing interest as a potential target across several cardiovascular indications. However, the short half-life of its cognate ligands, the apelin peptides, is a limiting factor for pharmacological use. In this study, we systematically explored each position of apelin-13 to find the best position to cyclize the peptide, with the goal to improve its stability while optimizing its binding affinity and signaling profile. Macrocyclic analogues showed a remarkably higher stability in rat plasma (half-life > 3 h versus 24 min for Pyr-apelin-13), accompanied with improved affinity (analogue 15, Ki 0...
February 20, 2018: Journal of Medicinal Chemistry
Ya Hao, Na Yang, Da Teng, Xiumin Wang, Ruoyu Mao, Jianhua Wang
Lactoferricin (Lfcin), a multifunction short peptide with a length of 25 residues, is derived from the whey protein lactoferrin by acidic pepsin hydrolysis. It has potent nutritional enhancement, antimicrobial, anticancer, antiviral, antiparasitic, and anti-inflammatory activities. This review describes the research advantages of the above biological functions, with attention to the molecular design and modification of Lfcin. In this examination of design and modification studies, research on the identification of Lfcin active derivatives and crucial amino acid residues is also reviewed...
February 17, 2018: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
Eunseon Oh, Yuhong Liu, Mahesh V Sonar, Diane Merry, Eric Wickstrom
Huntington's disease (HD) is an autosomal-dominant neurodegenerative genetic disorder caused by CAG repeat expansion in exon 1 of the HTT gene. Expression of the mutant gene results in the production of a neurotoxic polyglutamine (polyQ)-expanded huntingtin (Htt) protein. Clinical trials of knockdown therapy of mutant polyglutamine-encoding HTT mRNA in Huntington's disease (HD) have begun. To measure HTT mRNA knockdown effectiveness in human cells, we utilized a fluorescent hybridization imaging agent specific to the region encompassing the human HTT mRNA initiation codon...
February 16, 2018: Bioconjugate Chemistry
Catherine Fagundez, Diver Sellanes, Gloria Lourdes Serra
The results from the synthesis of peptides by Fmoc/SPPS on a 2-CTC resin and then lactamization in solution or solid phase for the preparation of cyclopeptides are presented. Both procedures allow the synthesis of the desired compounds in good to very good yield and with high cyclization efficiency for on-resin macrocyclization. In addition, the activities of the corresponding cyclopeptides against the chloroquine-resistant K1 strain of Plasmodium falciparum were evaluated. Cyclo-Cys(Trt)-Gly-Thr(tBu)-Gly-Cys(Trt)-Gly showed potent in vitro and selective activity against this parasite, EC50 = 28 nM...
February 15, 2018: ACS Combinatorial Science
Can M Buldun, Jisoo Jean, Michael R Bedford, Mark Howarth
Simple efficient reactions for connecting biological building-blocks open up many new possibilities. Here we have designed SnoopLigase, a protein which catalyzes site-specific transamidation, forming an isopeptide bond with up to 99% efficiency between two peptide tags, SnoopTagJr and DogTag. We initially developed these components by three-part splitting of the Streptococcus pneumoniae adhesin RrgA. The units were then engineered, guided by structure, bioinformatic analysis of sequence homology, and computational prediction of stability...
February 6, 2018: Journal of the American Chemical Society
Tyler A Wilson, Robert J Tokarski, Peter Sullivan, Robert M Demoret, Jimmy Orjala, L Harinantenaina Rakotondraibe, James R Fuchs
The human 20S proteasome inhibitor scytonemide A (1), a macrocyclic imine originally isolated from the cyanobacterium Scytonema hofmanni, was synthesized via a biomimetic solid-phase peptide synthesis (SPPS) approach employing the Weinreb AM resin. Utilizing this approach, cyclization of the protected heptapeptide via formation of the imine bond occurred spontaneously upon cleavage from the resin in the presence of a reducing agent and subsequent aqueous workup. The final deprotection step necessary to produce the natural product was accomplished under slightly basic conditions, facilitating cleavage of the silyl ether group while leaving the macrocycle intact...
February 5, 2018: Journal of Natural Products
Tom Meuleman, James Dunlop, Anna Owsianka, Helmus Van De Langemheen, Arvind H Patel, Rob Liskamp
Mimicry of the binding interface of antibody-antigen interactions using peptide-based modulators (i.e. epitope mimics) has promising applications for vaccine design. These epitope mimics can be synthesized in a streamlined and straightforward fashion, thereby allowing for high-throughput analysis. The design of epitope mimics is highly influenced by their spatial configuration and structural conformation. It is widely assumed that for proper mimicry sufficient conformational constraints have to be implemented...
January 31, 2018: Bioconjugate Chemistry
Min Yang, Haofei Hong, Shaozhong Liu, Xinrui Zhao, Zhimeng Wu
Chitosan macro-particles prepared by the neutralization method were applied to Sortase A (SrtA) immobilization using glutaraldehyde as a crosslinking agent. The particles were characterized by Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). Response surface methodology (RSM) was employed to optimize the immobilization process. An average specific activity of 3142 U (mg protein)-1 was obtained under optimized immobilization conditions (chitosan concentration 3%, SrtA concentration 0...
January 19, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
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