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51.
Matthew N. Idso Ajay Suresh Akhade Mario L. Arrieta-Ortiz Bert T. Lai Vivek Srinivas James P. Hopkins Jr. Ana Oliveira Gomes Naeha Subramanian Nitin Baliga James R. Heath 《Chemical science》2020,11(11):3054
Antibiotic resistant infections are projected to cause over 10 million deaths by 2050, yet the development of new antibiotics has slowed. This points to an urgent need for methodologies for the rapid development of antibiotics against emerging drug resistant pathogens. We report on a generalizable combined computational and synthetic approach, called antibody-recruiting protein-catalyzed capture agents (AR-PCCs), to address this challenge. We applied the combinatorial protein catalyzed capture agent (PCC) technology to identify macrocyclic peptide ligands against highly conserved surface protein epitopes of carbapenem-resistant Klebsiella pneumoniae, an opportunistic Gram-negative pathogen with drug resistant strains. Multi-omic data combined with bioinformatic analyses identified epitopes of the highly expressed MrkA surface protein of K. pneumoniae for targeting in PCC screens. The top-performing ligand exhibited high-affinity (EC50 ∼50 nM) to full-length MrkA, and selectively bound to MrkA-expressing K. pneumoniae, but not to other pathogenic bacterial species. AR-PCCs that bear a hapten moiety promoted antibody recruitment to K. pneumoniae, leading to enhanced phagocytosis and phagocytic killing by macrophages. The rapid development of this highly targeted antibiotic implies that the integrated computational and synthetic toolkit described here can be used for the accelerated production of antibiotics against drug resistant bacteria.Antibody-recruiting protein-catalyzed capture agent (AR-PCCs) are a new class of all-synthetic and highly targeted antibiotics that recruit endogenous immune responses to eliminate drug-resistant microbes. 相似文献
52.
The 6-hydroperoxy-1,4-cyclooctadiene (), which is formed in the photosensitized oxygenation of 1,5-cyclooctadiene (), affords on further singlet oxygenation 5,8-dihydroperoxy-1,3-cyclooctadiene (), which via triphenylphosphine reduction leads to -5,8-dihydroxy-1,3-cyclooctadiene () and subsequent pyridinium chlorochromate oxidation to 1,3-cyclooctadien-5,8-dione (). 相似文献
53.
Arya DP Micovic L Charles I Coffee RL Willis B Xue L 《Journal of the American Chemical Society》2003,125(13):3733-3744
Neomycin is the most effective aminoglycoside (groove binder) in stabilizing a DNA triple helix. It stabilizes TAT, as well as mixed base DNA triplexes, better than known DNA minor groove binders (which usually destabilize the triplex) and polyamines. Neomycin selectively stabilizes the triplex (in the presence of salt), without any effect on the DNA duplex. (1) Triplex stabilization by neomycin is salt dependent (increased KCl and MgCl(2) concentrations decrease neomycin's effectiveness, at a fixed drug concentration). (2) Triplex stabilization by neomycin is pH dependent (increased pH decreases neomycin's effectiveness, at a fixed drug concentration). (3) CD binding studies indicate approximately 5-7 base triplets/drug apparent binding site, depending upon the structure/sequence of the triplex. (4) Neomycin shows nonintercalative groove binding to the DNA triplex, as evident from viscometric studies. (5) Neomycin shows a preference for stabilization of TAT triplets but can also accommodate CGC(+) triplets. (6) Isothermal titration calorimetry (ITC) studies reveal an association constant of approximately 2 x 10(5) M(-)(1) between neomycin and an intramolecular triplex and a higher K(a) for polydA.2polydT. (7) Binding/modeling studies show a marked preference for neomycin binding to the larger W-H groove. Ring I/II amino groups and ring IV amines are proposed to be involved in the recognition process. (8) The novel selectivity of neomycin is suggested to be a function of its charge and shape complementarity to the triplex W-H groove, making neomycin the first molecule that selectively recognizes a triplex groove over a duplex groove. 相似文献
54.
Integrated Transmission Electron and Single‐Molecule Fluorescence Microscopy Correlates Reactivity with Ultrastructure in a Single Catalyst Particle 下载免费PDF全文
Frank C. Hendriks Sajjad Mohammadian Dr. Zoran Ristanović Dr. Sam Kalirai Dr. Florian Meirer Prof. Dr. Eelco T. C. Vogt Dr. Pieter C. A. Bruijnincx Prof. Dr. Hans C. Gerritsen Prof. Dr. Bert M. Weckhuysen 《Angewandte Chemie (International ed. in English)》2018,57(1):257-261
Establishing structure–activity relationships in complex, hierarchically structured nanomaterials, such as fluid catalytic cracking (FCC) catalysts, requires characterization with complementary, correlated analysis techniques. An integrated setup has been developed to perform transmission electron microscopy (TEM) and single‐molecule fluorescence (SMF) microscopy on such nanostructured samples. Correlated structure–reactivity information was obtained for 100 nm thin, microtomed sections of a single FCC catalyst particle using this novel SMF‐TEM high‐resolution combination. High reactivity in a thiophene oligomerization probe reaction correlated well with TEM‐derived zeolite locations, while matrix components, such as clay and amorphous binder material, were found not to display activity. Differences in fluorescence intensity were also observed within and between distinct zeolite aggregate domains, indicating that not all zeolite domains are equally active. 相似文献
55.
Dr. Rik De Clercq Prof. Michiel Dusselier Dr. Ekaterina Makshina Prof. Bert F. Sels 《Angewandte Chemie (International ed. in English)》2018,57(12):3074-3078
A new route to lactide, which is a key building block of the bioplastic polylactic acid, is proposed involving a continuous catalytic gas‐phase transesterification of renewable alkyl lactates in a scalable fixed‐bed setup. Supported TiO2/SiO2 catalysts are highly selective to lactide, with only minimal lactide racemization. The solvent‐free process allows for easy product separation and recycling of unconverted alkyl lactates and recyclable lactyl intermediates. The catalytic activity of TiO2/SiO2 catalysts was strongly correlated to their optical properties by DR UV/Vis spectroscopy. Catalysts with high band‐gap energy of the supported TiO2 phase, indicative of a high surface spreading of isolated Ti centers, show the highest turnover frequency per Ti site. 相似文献
56.
Affinity capillary electrophoresis to evaluate the complex formation between poliovirus and nanobodies 下载免费PDF全文
Hadewych Halewyck Lise Schotte Iuliana Oita Bert Thys Ann Van Eeckhaut Yvan Vander Heyden Bart Rombaut 《Journal of separation science》2014,37(24):3729-3737
It was demonstrated that nanobodies with an in vitro neutralizing activity against poliovirus type 1 interact with native virions. Here, the use of capillary electrophoresis was investigated as an alternative technique for the evaluation of the formation of nanobody–poliovirus complexes, and therefore predicting the in vitro neutralizing activity of the nanobodies. The macromolecules are preincubated offline in a specific nanobody‐to‐virus ratio and analyzed by capillary electrophoresis with UV detection. At low nanobody‐to‐virus ratios, a clear shift in migration time of the viral peak was observed. A broad peak was obtained, indicating the presence of a heterogeneous population of nanobody–virion complexes, caused by the binding of different numbers of nanobodies to the virus particle. At elevated nanobody‐to‐virus ratios, a cluster of peaks appeared, showing an additional increase in migration times. It was shown that, at these high molar excesses, aggregates were formed. The developed capillary electrophoresis method can be used as a rapid, qualitative screening for the affinity between poliovirus and nanobodies, based on a clearly visible and measurable shift in migration time. The advantages of this technique include that there is no need for antigen immobilization as in enzyme‐linked immunosorbent assays or surface plasmon resonance for the use of radiolabeled virus or for the performance of labor‐ and time‐intensive plaque‐forming neutralization assays. 相似文献
57.
58.
A mass‐conservative staggered immersed boundary model for solving the shallow water equations on complex geometries 下载免费PDF全文
Alberto Canestrelli Aukje Spruyt Bert Jagers Rudy Slingerland Mart Borsboom 《国际流体数值方法杂志》2016,81(3):151-177
In this work, an approach is proposed for solving the 3D shallow water equations with embedded boundaries that are not aligned with the underlying horizontal Cartesian grid. A hybrid cut‐cell/ghost‐cell method is used together with a direction‐splitting implicit solver: Ghost cells are used for the momentum equations in order to prescribe the correct boundary condition at the immersed boundary, while cut cells are used in the continuity equation in order to conserve mass. The resulting scheme is robust, does not suffer any time step limitation for small cut cells, and conserves fluid mass up to machine precision. Moreover, the solver displays a second‐order spatial accuracy, both globally and locally. Comparisons with analytical solutions and reference numerical solutions on curvilinear grids confirm the quality of the method. Copyright © 2015 John Wiley & Sons, Ltd. 相似文献
59.
60.
Apperloo JJ Groenendaal LB Verheyen H Jayakannan M Janssen RA Dkhissi A Beljonne D Lazzaroni R Brédas JL 《Chemistry (Weinheim an der Bergstrasse, Germany)》2002,8(10):2384-2396
The optical and redox properties of a series of 3,4-ethylenedioxythiophene oligomers (EDOTn, n=1-4) and their beta,beta'-unsubstituted analogues (Tn, n=1-4) are described. Both series are end capped with phenyl groups to prevent irreversible alpha-coupling reactions during oxidative doping. Absorption and fluorescence spectra of both series reveal a significantly higher degree of intrachain conformational order in the EDOTn oligomers. Oxidation potentials (E(PA1) and E(PA2)) determined by cyclic voltammetry reveal that those of EDOTn are significantly lower than the corresponding Tn oligomers as a consequence of the electron-donating 3,4-ethylenedioxy substitution. Linear fits of E(PA1) and E(PA2) versus the reciprocal number of double bonds reveal significantly steeper slopes for the EDOTn than for the Tn oligomers. This could indicate a more effective conjugation for the EDOTn series, confirmed by the fact that coalescence of E(PA1) and E(PA2) is reached already at relatively short chain lengths ( approximately 5 EDOT units) in contrast to the Tn series (>10 thiophene units). The stepwise chemical oxidation of the EDOTn and Tn oligomers in solution was carried out to obtain radical cations and dications. The energies of the optical transitions of the radical cations and dications as determined by UV/Vis/NIR spectroscopy were similar for the two series. These spectroscopic observations are consistent with quantum-chemical calculations performed on the singly charged molecules. Cooling solutions containing T2.+, T3.+, EDOT2.+, and EDOT3.+ revealed the reversible formation of dimers, albeit with a somewhat different tendency, expressed in the values for the dimerization enthalpy. 相似文献