Nanomolar small-molecule detection using a genetically encoded<sup>129</sup>Xe NMR contrast agent

Roose, Benjamin W.; Zemerov, Serge D.; Dmochowski, Ivan J.

doi:10.1039/c7sc03601a

Cited by 28 publications

(42 citation statements)

References 51 publications

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“…Depolarized Xe rapidly exchanges into solvent, depolarizing the reservoir of bulk Xe which, in turn, generates MR contrast. Our lab has employed hyper-CEST to study Xe interactions with spores (Bai et al, 2014) as well as the proteins TEM-1 β-lactamase (Bla) (Wang et al, 2016) and maltose binding protein (MBP) (Roose, Zemerov, & Dmochowski, 2017). Representative hyper-CEST z-spectra for 80 μM Bla and MBP in PBS are shown in Fig.…”

Section: Xe Nmrmentioning

confidence: 99%

Xenon–Protein Interactions: Characterization by X-Ray Crystallography and Hyper-CEST NMR

Roose

Zemerov

Dmochowski

2018

Methods in Enzymology

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The physiological activity of xenon has long been recognized, though the exact nature of its interactions with biomolecules remains poorly understood. Xe is an inert noble gas, but can act as a general anesthetic, most likely by binding internal hydrophobic cavities within proteins. Understanding Xe-protein interactions, therefore, can provide crucial insight regarding the mechanism of Xe anesthesia and potentially other general anesthetic agents. Historically, Xe-protein interactions have been studied primarily through X-ray crystallography and nuclear magnetic resonance (NMR). In this chapter, we first describe our methods for preparing Xe derivatives of protein crystals and identifying Xe-binding sites. Second, we detail our procedure for Xe hyper-CEST NMR spectroscopy, a versatile NMR technique well suited for characterizing the weak, transient nature of Xe-protein interactions.

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Section: Xe Nmrmentioning

confidence: 99%

Xenon–Protein Interactions: Characterization by X-Ray Crystallography and Hyper-CEST NMR

Roose

Zemerov

Dmochowski

2018

Methods in Enzymology

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“…[11][12][13] CB6 is synthetically difficult to funactionalize and also suffers from limited solubility unless solubilizing counterions are used which were found to have an unwanted effect on exchange efficiency. Protein structures for trapping Xe have also been investigated [14][15][16] as a genetically expressible host version, but their complexity makes it rather tedious to further tune the chemical shift and exchange properties through chemical engineering. Thus, this currently active field of method development for biomedical imaging applications is seeking additional concepts for Xe hosts based on simple building blocks to extend the range of sensor applications.Pillar [5]arenes are another class of macrocyclic hosts having a relatively rigid cylindrical structure capable of encapsulating both charged and neutral guests.…”

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confidence: 99%

High Exchange Rate Complexes of ¹²⁹Xe with Water‐Soluble Pillar[5]arenes for Adjustable Magnetization Transfer MRI

et al. 2018

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Macrocyclic host structures for generating transiently bound Xe have been used in various ultra-sensitive NMR and MRI applications for molecular sensing of biochemical analytes. They are based on hyperpolarized nuclei chemical exchange saturation transfer (Hyper-CEST). Here, we tested a set of water-soluble pillar[5]arenes with different counterions in order to compare their potential contrast agent abilities with that of cryptophane-A (CrA), the most widely used host for such purposes. The exchange of Xe with such compounds was found to be sensitive to the type of ions present in solution and can be used for switchable magnetization transfer (MT) contrast that arises from off-resonant pre-saturation. We demonstrate that the adjustable MT magnitude depends on the interplay of saturation parameters and found that the optimum MT contrast surpasses the CrA CEST performance at moderate saturation power. Since modification of such water-soluble pillar[5]arenes is straightforward, these compounds can be considered a promising platform for designing various sensors that may complement the field of Xe HyperCEST-based biosensing MRI.

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“…The solution is a system of exchange-coupled spin pools where both pools grow proportionately to keep their size ratio, f B , and, thus, the CEST efficiency constant. This approach is conceptually different from 1:1 Xe complex formation, protein-based sensors 18,19 or reversible chemical binding in 1 H CEST. We demonstrate ideal CEST performance through simple physical partitioning of a dissolved gas into a nano-sized volume ( Figure 1B), thereby introducing the concept of an "elastic" contrast agent for Hyper-CEST.…”

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confidence: 99%

Protein Nanostructures Produce Self-Adjusting Hyperpolarized Magnetic Resonance Imaging Contrast through Physical Gas Partitioning

Kunth

Witte

et al. 2018

ACS Nano

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Signal amplification strategies are critical for overcoming the intrinsically poor sensitivity of nuclear magnetic resonance (NMR) reporters in noninvasive molecular detection. A mechanism widely used for signal enhancement is chemical exchange saturation transfer (CEST) of nuclei between a dilute sensing pool and an abundant detection pool. However, the dependence of CEST amplification on the relative size of these spin pools confounds quantitative molecular detection with a larger detection pool typically making saturation transfer less efficient. Here we show that a recently discovered class of genetically encoded nanoscale reporters for 129 Xe magnetic resonance overcomes this fundamental limitation through an elastic binding capacity for NMR-active nuclei. This approach pairs high signal amplification from hyperpolarized spins with ideal, self-adjusting saturation transfer behavior as the overall spin ensemble changes in size. These reporters are based on gas vesicles, i.e., microbe-derived, gas-filled protein nanostructures. We show that the xenon fraction that partitions into gas vesicles follows the ideal gas law, allowing the signal transfer under hyperpolarized xenon chemical exchange saturation transfer (Hyper-CEST) imaging to scale linearly with the total xenon ensemble. This conceptually distinct elastic response allows the production of quantitative signal contrast that is robust to variability in the concentration of xenon, enabling virtually unlimited improvement in absolute contrast with increased xenon delivery, and establishing a unique principle of operation for contrast agent development in emerging biochemical and in vivo applications of hyperpolarized NMR and magnetic resonance imaging.

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Nanomolar small-molecule detection using a genetically encoded¹²⁹Xe NMR contrast agent

Abstract: Genetically encoded magnetic resonance imaging (MRI) contrast agents enable non-invasive detection of specific biomarkers in vivo.

Cited by 28 publications

References 51 publications

Xenon–Protein Interactions: Characterization by X-Ray Crystallography and Hyper-CEST NMR

Xenon–Protein Interactions: Characterization by X-Ray Crystallography and Hyper-CEST NMR

High Exchange Rate Complexes of ¹²⁹Xe with Water‐Soluble Pillar[5]arenes for Adjustable Magnetization Transfer MRI

Protein Nanostructures Produce Self-Adjusting Hyperpolarized Magnetic Resonance Imaging Contrast through Physical Gas Partitioning

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Nanomolar small-molecule detection using a genetically encoded129Xe NMR contrast agent

Abstract: Genetically encoded magnetic resonance imaging (MRI) contrast agents enable non-invasive detection of specific biomarkers in vivo.

Cited by 28 publications

References 51 publications

Xenon–Protein Interactions: Characterization by X-Ray Crystallography and Hyper-CEST NMR

Xenon–Protein Interactions: Characterization by X-Ray Crystallography and Hyper-CEST NMR

High Exchange Rate Complexes of 129Xe with Water‐Soluble Pillar[5]arenes for Adjustable Magnetization Transfer MRI

Protein Nanostructures Produce Self-Adjusting Hyperpolarized Magnetic Resonance Imaging Contrast through Physical Gas Partitioning

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Nanomolar small-molecule detection using a genetically encoded¹²⁹Xe NMR contrast agent

High Exchange Rate Complexes of ¹²⁹Xe with Water‐Soluble Pillar[5]arenes for Adjustable Magnetization Transfer MRI