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Lactam constraint

Dillon T Flood, Nicholas L Yan, Philip E Dawson
Amino-γ-lactam (Agl) bridged dipeptides, commonly known as Freidinger Lactams, have been shown to constrain peptide backbone topology and stabilize Type II' β-turns. The utility of these links as peptide constraints has inspired new approaches to their incorporation into complex peptides and peptoids, all of which require harsh reaction conditions or protecting groups and limit their use on unprotected peptides and proteins. Here, we employ a mild and selective alkylation of selenomethionine in acidic aqueous solution, followed by immobilization of the alkylated peptide on to bulk reversed-phase C18 silica, and base-induced lactamization in DMSO...
May 23, 2018: Angewandte Chemie
Katrien Forier, Virginie Van Heck, Mieke Carlier, Eva Van Braeckel, Sabine Van Daele, Frans De Baets, Petra Schelstraete, Filomeen Haerynck, Veronique Stove, Leen Van Simaey, Mario Vaneechoutte, Alain G Verstraete
Objectives: Antibiotic therapy is of vital importance for the control of infectious exacerbations in cystic fibrosis (CF) patients. However, very little is known regarding the fraction of systemically administered antibiotics reaching the lower respiratory tract secretions. We developed and validated a method to measure the concentrations of piperacillin, ceftazidime, meropenem and aztreonam in CF sputum, and present the validation data. Methods: Ultra-performance LC coupled to tandem MS was used...
January 1, 2018: Journal of Antimicrobial Chemotherapy
Ruiqing Xiao, Eric L Dane, Jialiu Zeng, Christopher J McKnight, Mark W Grinstaff
The design and synthesis of amide-linked saccharide oligomers and polymers, which are predisposed to fold into specific ordered secondary structures, is of significant interest. Herein, right-handed helical poly amido-saccharides (PASs) with β-N-(1→2)-d-amide linkages are synthesized by the anionic ring-opening polymerization of an altrose β-lactam monomer (alt-lactam). The right-handed helical conformation is engineered into the polymers by preinstalling the β configuration of the lactam ring in the monomer via the stereospecific [2+2] cycloaddition of trichloroacetyl isocyanate with a d-glycal possessing a 3-benzyloxy group oriented to the α-face of the pyranose...
October 11, 2017: Journal of the American Chemical Society
Britta K Sundquist, Brady J Bowen, Uwa Otabor, Jocelyn Celestin, Paul C Sorum
OBJECTIVES: To promote penicillin allergy testing in an outpatient setting in patients labeled as penicillin allergic, to determine the number of those who are truly allergic, evaluate patient satisfaction with the testing, and educate both patients and clinicians about testing. METHODS: Patients with a history of penicillin allergy listed in their EHR were screened and recruited by their primary care office and referred for penicillin allergy testing. The results of allergy testing and patient satisfaction after testing were the main outcomes...
November 2017: Postgraduate Medicine
Saskia Neukirchen, Viktoria Krieger, Cornelia Roschger, Mario Schubert, Brigitta Elsässer, Chiara Cabrele
Synthetic helical peptides are valuable scaffolds for the development of modulators of protein-protein interactions involving helical motifs. Backbone-to-side chain or side chain-to-side chain constraints have been and still are intensively exploited to stabilize short α-helices. Very often, these constraints have been combined with backbone modifications induced by Cα-tetrasubstituted, β-, or γ-amino acids, which facilitate the α-peptide or α/β/γ-peptide adopting an α-helical conformation. In this work, we investigated the helical character of octapeptides that were cyclized by a Lys-Asp-(i,i + 4)-lactam bridge...
July 2017: Journal of Peptide Science: An Official Publication of the European Peptide Society
Ramya Salimraj, Lihong Zhang, Philip Hinchliffe, Elizabeth M H Wellington, Jürgen Brem, Christopher J Schofield, William H Gaze, James Spencer
β-Lactamase production increasingly threatens the effectiveness of β-lactams, which remain a mainstay of antimicrobial chemotherapy. New activities emerge through both mutation of previously known β-lactamases and mobilization from environmental reservoirs. The spread of metallo-β-lactamases (MBLs) represents a particular challenge because of their typically broad-spectrum activities encompassing carbapenems, in addition to other β-lactam classes. Increasingly, genomic and metagenomic studies have revealed the distribution of putative MBLs in the environment, but in most cases their activity against clinically relevant β-lactams and, hence, the extent to which they can be considered a resistance reservoir remain uncharacterized...
October 2016: Antimicrobial Agents and Chemotherapy
C Mirande, I Canard, S Buffet Croix Blanche, J-P Charrier, A van Belkum, M Welker, S Chatellier
Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) has been introduced as an identification procedure for bacteria and fungi. The MALDI-TOF MS-based analysis of resistance to β-lactam antibiotics has been applied to detect hydrolysis of carbapenems by different bacterial strains. However, the detection of enzymatic carbapenem degradation by MALDI-TOF MS lacks well-standardized protocols and several methods and models of interpretation using different calculations of ratio-of-peak intensities have been described in the literature...
November 2015: European Journal of Clinical Microbiology & Infectious Diseases
Jenna R Brown, Dennis R Livesay
β-lactamases are bacterial enzymes that confer resistance to β-lactam antibiotics, such as penicillins and cephalosporins. There are four classes of β-lactamase enzymes, each with characteristic sequence and structure properties. Enzymes from class A are the most common and have been well characterized across the family; however, less is known about how physicochemical properties vary across the C and D families. In this report, we compare the dynamical properties of four AmpC (class C) β-lactamases using our distance constraint model (DCM)...
2015: PloS One
Nicholas J Croucher, Lisa Kagedan, Claudette M Thompson, Julian Parkhill, Stephen D Bentley, Jonathan A Finkelstein, Marc Lipsitch, William P Hanage
Streptococcus pneumoniae isolates typically express one of over 90 immunologically distinguishable polysaccharide capsules (serotypes), which can be classified into "serogroups" based on cross-reactivity with certain antibodies. Pneumococci can alter their serotype through recombinations affecting the capsule polysaccharide synthesis (cps) locus. Twenty such "serotype switching" events were fully characterised using a collection of 616 whole genome sequences from systematic surveys of pneumococcal carriage...
March 2015: PLoS Genetics
Nicolas Auberger, Margherita Di Pisa, Maud Larregola, Gérard Chassaing, Elisa Peroni, Solange Lavielle, Anna-Maria Papini, Olivier Lequin, Jean-Maurice Mallet
The Glaser-Eglinton reaction between either two C or N propargylglycine (Pra or NPra) amino acids, in the presence of copper(II), led to cyclic hexa- and octapeptides constrained by a butadiyne bridge. The on-resin cyclization conditions were analyzed and optimized. The consequences of this type of constraint on the three dimensional structure of these hexapeptides and octapeptides were analyzed in details by NMR and molecular dynamics. We show that stabilized short cyclic peptides could be readily prepared via the Glaser oxidative coupling either with a chiral (Pra), or achiral (NPra) residue...
December 15, 2014: Bioorganic & Medicinal Chemistry
Marcelo Der Torossian Torres, Adriana Farias Silva, Leandro de Souza Silva, Ana Acácia de Sá Pinheiro, Vani Xavier Oliveira
The anti-plasmodial activity of conformationally restricted analogs of angiotensin II against Plasmodium gallinaceum has been described. To observe activity against another Plasmodium species, invasion of red blood cells by Plasmodium falciparum was analyzed. Analogs restricted with lactam or disulfide bridges were synthesized to determine their effects and constraints in the peptide-parasite interaction. The analogs were synthesized using tert-butoxycarbonyl and fluoromethoxycarbonyl solid phase methods, purified by liquid chromatography, and characterized by mass spectrometry...
January 2015: Journal of Peptide Science: An Official Publication of the European Peptide Society
Ngoc-Duc Doan, Robert Hopewell, William D Lubell
The synthesis of N-aminoimidazolidin-2-one (Aid) peptidomimetics has been achieved by alkylation of the urea nitrogen of a semicarbazone residue using ethylene bromide. The Aid scaffold combines electronic and structural constraints to rigidify the peptide backbone in the equivalent of an aza variant of a Freidinger-Veber lactam. The syntheses and isolation of 25 Aid peptides, including eight GHRP-6 analogues, are reported to demonstrate the utility of this method for controlling conformation.
April 18, 2014: Organic Letters
Dong Xiao, Anandan Palani, Xianhai Huang, Michael Sofolarides, Wei Zhou, Xiao Chen, Robert Aslanian, Zhuyan Guo, James Fossetta, Fang Tian, Prashant Trivedi, Peter Spacciapoli, Charles E Whitehurst, Daniel Lundell
Conformation restriction of linear N-alkylanilide MK2 inhibitors to their E-conformer was developed. This strategy enabled rapid advance in identifying a series of potent non-ATP competitive inhibitors that exhibited cell based activity in anti-TNFα assay.
June 1, 2013: Bioorganic & Medicinal Chemistry Letters
Agnieszka Witosińska, Bogdan Musielak, Paweł Serda, Maria Owińska, Barbara Rys
The title compounds were synthesized, and their structure and conformational behavior in solution (NMR and DFT), in the gas phase (DFT), and, for some of them, in the solid state (X-ray) were investigated. The variable-temperature NMR spectra were employed to determine the conformational equilibria and the activation energy of the conformational changes of the eight-membered ring. The coalescence effects are assigned to racemization of the chiral ground-state conformation with a ring inversion barrier in the range of 38-100 kJ mol(-1) depending on the relative setting of the two strong conformational constraints: benzoannulation and the amide function...
November 2, 2012: Journal of Organic Chemistry
Andrew R Buller, Jason W Labonte, Michael F Freeman, Nathan T Wright, Joel F Schildbach, Craig A Townsend
cis-Autoproteolysis is a post-translational modification necessary for the function of ThnT, an enzyme involved in the biosynthesis of the β-lactam antibiotic thienamycin. This modification generates an N-terminal threonine nucleophile that is used to hydrolyze the pantetheinyl moiety of its natural substrate. We determined the crystal structure of autoactivated ThnT to 1.8Å through X-ray crystallography. Comparison to a mutationally inactivated precursor structure revealed several large conformational rearrangements near the active site...
September 28, 2012: Journal of Molecular Biology
Maoqing Dong, Jerez A Te, Xiequn Xu, Jinhui Wang, Delia I Pinon, Laura Storjohann, Andrew J Bordner, Laurence J Miller
The natural ligands for family B G protein-coupled receptors are moderate-length linear peptides having diffuse pharmacophores. The amino-terminal regions of these ligands are critical for biological activity, with their amino-terminal truncation leading to production of orthosteric antagonists. The carboxyl-terminal regions of these peptides are thought to occupy a ligand-binding cleft within the disulfide-bonded amino-terminal domains of these receptors, with the peptides in amphipathic helical conformations...
September 27, 2011: Biochemistry
Kenneth M Boy, Jason M Guernon, Jianliang Shi, Jeremy H Toyn, Jere E Meredith, Donna M Barten, Catherine R Burton, Charles F Albright, Jovita Marcinkeviciene, Andrew C Good, Andrew J Tebben, Jodi K Muckelbauer, Daniel M Camac, Kimberley A Lentz, Joanne J Bronson, Richard E Olson, John E Macor, Lorin A Thompson
The synthesis, evaluation, and structure-activity relationships of a class of γ-lactam 1,3-diaminopropan-2-ol transition-state isostere inhibitors of BACE are discussed. Two strategies for optimizing lead compound 1a are presented. Reducing the overall size of the inhibitors resulted in the identification of γ-lactam 1i, whereas the introduction of conformational constraint on the prime-side of the inhibitor generated compounds such as the 3-hydroxypyrrolidine inhibitor 28n. The full in vivo profile of 1i in rats and 28n in Tg 2576 mice is presented...
November 15, 2011: Bioorganic & Medicinal Chemistry Letters
Rob M J Liskamp, Dirk T S Rijkers, John A W Kruijtzer, Johan Kemmink
Despite their enormous diversity in biological function and structure, peptides and proteins are endowed with properties that have induced and stimulated the development of peptidomimetics. Clearly, peptides can be considered as the "stem" of a phylogenetic molecular development tree from which branches of oligomeric peptidomimetics such as peptoids, peptidosulfonamides, urea peptidomimetics, as well as β-peptides have sprouted. It is still a challenge to efficiently synthesize these oligomeric species, and study their structural and biological properties...
July 25, 2011: Chembiochem: a European Journal of Chemical Biology
D S Perlow, R M Freidinger
Lactam-bridged dipeptides are useful tools for the introduction of conformational constraint in higher peptides. General methods have been devised for the synthesis of dipeptides having five-, six-, and seven-membered ring constraints (1,2). This chapter will focus on four synthetic paths from protected chiral a-amino acids to lactams that involve intramolecular alkylation, intermolecular alkylation, intramolecular acylation, and condensation with formaldehyde for a one carbon unit insertion.
1999: Methods in Molecular Medicine
Marion Tarbe, Itxaso Azcune, Eva Balentová, John J Miles, Emily E Edwards, Kim M Miles, Priscilla Do, Brian M Baker, Andrew K Sewell, Jesus M Aizpurua, Céline Douat-Casassus, Stéphane Quideau
β-Lactam peptides were envisioned as conformational constraints in antigenic peptides (APs). Three different β-lactam tripeptides of varying flexibility were prepared in solution and incorporated in place of the central part of the altered melanoma associated antigenic peptide Leu(27)-Melan-A(26-35) using solid phase synthesis techniques. Upon TFA cleavage from the solid support, an unexpected opening of the β-lactam ring occurred with conservation of the amide bond. After adaptation of the solid phase synthesis strategy, β-lactam peptides were successfully obtained and both opened and closed forms were evaluated for their capacity to bind to the antigen-presenting class-I MHC HLA-A2 protein system...
December 7, 2010: Organic & Biomolecular Chemistry
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