Semiconducting nanowires have the potential to function as highly sensitive and selective sensors for the label-free detection of low concentrations of pathogenic microorganisms. Successful solution-phase nanowire sensing has been demonstrated for ions, small molecules, proteins, DNA and viruses; however, 'bottom-up' nanowires (or similarly configured carbon nanotubes) used for these demonstrations require hybrid fabrication schemes, which result in severe integration issues that have hindered widespread application. Alternative 'top-down' fabrication methods of nanowire-like devices produce disappointing performance because of process-induced material and device degradation. Here we report an approach that uses complementary metal oxide semiconductor (CMOS) field effect transistor compatible technology and hence demonstrate the specific label-free detection of below 100 femtomolar concentrations of antibodies as well as real-time monitoring of the cellular immune response. This approach eliminates the need for hybrid methods and enables system-scale integration of these sensors with signal processing and information systems. Additionally, the ability to monitor antibody binding and sense the cellular immune response in real time with readily available technology should facilitate widespread diagnostic applications.
O-Aryloxycarbonyl hydroxamates represent a new class of β-lactamase inhibitors. N-Benzyloxycarbonyl-O-(phenoxycarbonyl) hydroxylamine, for example, inactivates the class C Enterobacter cloacae P99 β-lactamase with a rate constant of 6.1 × 103 s-1 M-1; approximately two turnover events accompany the inhibition. N-Benzyloxycarbonyl-O-[(3-carboxyphenoxy)carbonyl] hydroxylamine is comparably effective. These compounds also inactivate the class A TEM β-lactamase. A crystal structure of the inactivated AmpC enzyme, another class C β-lactamase, reveals that the active site has become cross-linked by a carbamate bridge spanning Ser64, the active site nucleophile, and Lys315, a conserved active site residue.
The design, synthesis and structural analysis of a new foldamer that mimics an extended β-sheet is presented. The non-peptidic mimetic is based on a series of 2,2-disubstituted-indolin-3-one groups linked through their 4,7 positions by an alkyne spacer. An intramolecular hydrogen bond between the carbonyl of one indolinone subunit and the proximal NH of another subunit imposes a conformation that mimics the side chain positioning on a β-strand. X-ray crystallographic studies support the presence of this intramolecular hydrogen bond. The described approach allows extension of the scaffold to longer oligomers that will form the basis of new mimetics for the disruption of therapeutically relevant protein-protein interactions that rely on the contacts of side chain residues on two β-strands.In recent years there has been much interest in the development of synthetic mimics of protein secondary structure. These molecules have the potential to act as effective agents in the disruption of protein-protein interactions involved in disease processes. In particular, substantial progress has been made in the mimicry of α-helix structure and function with several innovative peptidic and non-peptidic scaffolds that reproduce the distance and angular projection of side chains on the helix. 1 Surprisingly, less work has been done towards the development of β-strand and β-sheet mimetics. Early examples have been based on conformationally constrained scaffolds that mimic an extended peptide. 2,3 In general, these approaches utilize a rigid template that stabilizes β-sheet structure between the attached peptide strands. The early work of Feigel showed that a biphenyl template can be used to induce β-sheet formation between two attached peptides. 4 This subsequently led to the design of templates such as epindolidiones 5 , dibenzofurans 6 , metallopeptides 7 , and oligoureas 8 each capable of positioning the peptides such that interstrand hydrogen bonding can occur. There is only one example of a truly non-peptidic β-strand mimetic which is the oligopyrrolinone scaffold from Smith. 9 As part of our interest in protein-protein interactions we sought to extend our synthetic approach to α-helix mimics to stretches of protein in a β-strand or β-sheet conformation. One biologically significant example of edge-edge contact between two β-strands is seen with the andrew.hamilton@yale.edu. Supporting Information Available: Experimental procedures, full characterization of all new compounds, and X-ray crystallographic analysis for 1 and 2. This material is available free of charge via the Internet at http://pubs.acs.org. oncoprotein Ras (or related Rap1A) and one of its key effector proteins, Raf1 kinase ( Figure 1) (pdb 1GUA). 10 Attenuation of Ras function is a major focus in the development of new cancer therapeutics and reinforces the need for structural mimetics that are able to disrupt this protein-protein interaction. In this paper we present the design, synthesis and structural analysis of a novel and potentially extendable ...
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