Design and mechanistic investigation of oxime-conjugated PAMAM dendrimers as the catalytic scavenger of reactive organophosphate

Bharathi, Sophia; Wong, Pamela; Desai, Ankur; Lykhytska, Olga; Choe, Veronica; Kim, Hannah; Thomas, Thommey P.; Baker, James R.; Choi, Seok Ki

doi:10.1039/c3tb21267j

Cited by 17 publications

(35 citation statements)

References 55 publications

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“…It is known that esterase enzymes can be phosphorylated at their nucleophilic serine residues upon exposure to organophosphates through a mechanism of inactivation followed by aging [31,32,33,34]. However, there was no precedence in the literature for the phosphorylation of the active site serine of BlaC, thus it was unknown whether the Ser-70 of BlaC could be irreversibly modified by a phosphorus ligand.…”

Section: Discussionmentioning

confidence: 99%

Crystal Structure of Phosphoserine BlaC from Mycobacterium tuberculosis Inactivated by Bis(Benzoyl) Phosphate

Moural

White

Choy

et al. 2019

IJMS

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Mycobacterium tuberculosis, the pathogen responsible for tuberculosis (TB), is the leading cause of death from infectious disease worldwide. The class A serine β-lactamase BlaC confers Mycobacterium tuberculosis resistance to conventional β-lactam antibiotics. As the primary mechanism of bacterial resistance to β-lactam antibiotics, the expression of a β-lactamase by Mycobacterium tuberculosis results in hydrolysis of the β-lactam ring and deactivation of these antibiotics. In this study, we conducted protein X-ray crystallographic analysis of the inactivation of BlaC, upon exposure to the inhibitor bis(benzoyl) phosphate. Crystal structure data confirms that serine β-lactamase is phosphorylated at the catalytic serine residue (Ser-70) by this phosphate-based inactivator. This new crystallographic evidence suggests a mechanism for phosphorylation of BlaC inhibition by bis(benzoyl) phosphate over acylation. Additionally, we confirmed that bis(benzoyl) phosphate inactivated BlaC in a time-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Crystal Structure of Phosphoserine BlaC from Mycobacterium tuberculosis Inactivated by Bis(Benzoyl) Phosphate

Moural

White

Choy

et al. 2019

IJMS

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“…Other scaffolds such as those prepared by PAM conjugation to a glucose [2] or β- Recently, several types of molecular scaffolds are designed and tested as effective chemical decontaminants for OP pesticides and nerve agents [119,121,[126][127][128]. These include α-nucleophile scaffolds prepared by conjugation with oxime [16,124], pyridinium aldoxime (PAM) [120,129,130] or hydroxamic acid (HA) [16,129,131]. Some of these have shown greater efficiency in topical decontamination of porcine skin exposed to POX ex vivo than Dekon 139 [16,124].…”

Section: Chemical Scavengersmentioning

confidence: 99%

“…They allow structural modifications with OP-reactive moieties on its peripheral branches as illustrated in Figure 8B. In this work, Bharathi et al describes PAM-conjugated G5 dendrimer and its ability to accelerate the rate of POX hydrolysis [130]. However, despite such effectiveness, their OP-reactive moieties may engage in undesired reactions with proteins and enzymes such as AChE.…”

Section: Metal Oxide Nanoparticlementioning

confidence: 99%

“…In topic summary, nanomaterials offer a variety of structural and functional properties that enable to address current unmet needs associated with OP exposure and intoxication. They have shown practical utilities in a broad range of applications from antidote drug delivery [86,87,89], protective material design [148], environmental decontamination [139] to therapeutic skin decontamination [37,117,118,130,144,149] as summarized in Table 2 and Table S1 (Supplementary Material). In topic summary, nanomaterials offer a variety of structural and functional properties that enable to address current unmet needs associated with OP exposure and intoxication.…”

Section: Metal Oxide Nanoparticlementioning

confidence: 99%

“…Nanomaterials are readily functionalized to create mechanisms for OP inactivation by which they can serve as OP scavengers [159]. This is illustrated with those nanoscavengers made of liposome [120,134,139], polymer [140,141], MOF [117,148], metal oxide [149][150][151] and dendrimer [37,130,155]. Their scavenging capability relies on reactive functionalities either present in unmodified nanomaterials such as photocatalytic metal oxides [149][150][151] or built additionally such as oximes [120,134], metal chelates [140,141], amines [148] or amino acids [155].…”

Section: Conclusion and Perspectivementioning

confidence: 99%

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Nanomaterial-Enabled Sensors and Therapeutic Platforms for Reactive Organophosphates

Choi

2021

Nanomaterials

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Unintended exposure to harmful reactive organophosphates (OP), which comprise a group of nerve agents and agricultural pesticides, continues to pose a serious threat to human health and ecosystems due to their toxicity and prolonged stability. This underscores an unmet need for developing technologies that will allow sensitive OP detection, rapid decontamination and effective treatment of OP intoxication. Here, this article aims to review the status and prospect of emerging nanotechnologies and multifunctional nanomaterials that have shown considerable potential in advancing detection methods and treatment modalities. It begins with a brief introduction to OP types and their biochemical basis of toxicity followed by nanomaterial applications in two topical areas of primary interest. One topic relates to nanomaterial-based sensors which are applicable for OP detection and quantitative analysis by electrochemical, fluorescent, luminescent and spectrophotometric methods. The other topic is directed on nanotherapeutic platforms developed as OP remedies, which comprise nanocarriers for antidote drug delivery and nanoscavengers for OP inactivation and decontamination. In summary, this article addresses OP-responsive nanomaterials, their design concepts and growing impact on advancing our capability in the development of OP sensors, decontaminants and therapies.

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High‐Throughput Label‐Free Enzymatic Assays Using Desorption Electrospray‐Ionization Mass Spectrometry

2020

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High-throughput (HT) enzymatic assays, which typically rely on labeled compounds and plate readers, are important for drug discovery. Mass spectrometry (MS) provides an alternative method of performing HT label-free assays. Here we demonstrate the use of a HT platform based on desorption electrospray ionization (DESI) MS for the labelfree study of enzymatic reactions directly from the bioassay matrix with an effective analysis time of 0.3 s per sample. This system allows for thorough analysis of the enzymatic process through monitoring of its substrate and product after an external calibration. We show the platform capabilities by an in-depth study of the acetylcholinesterase assay, including kinetic parameter determination, rapid inhibitor screening, and further characterization of positive hits (that is, IC 50 and K i), as well as inhibition-reactivation assays. We anticipate that the expansion of this platform has high potential impact in labelfree enzymology as well as in drug discovery.

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Design and mechanistic investigation of oxime-conjugated PAMAM dendrimers as the catalytic scavenger of reactive organophosphate

Cited by 17 publications

References 55 publications

Crystal Structure of Phosphoserine BlaC from Mycobacterium tuberculosis Inactivated by Bis(Benzoyl) Phosphate

Crystal Structure of Phosphoserine BlaC from Mycobacterium tuberculosis Inactivated by Bis(Benzoyl) Phosphate

Nanomaterial-Enabled Sensors and Therapeutic Platforms for Reactive Organophosphates

High‐Throughput Label‐Free Enzymatic Assays Using Desorption Electrospray‐Ionization Mass Spectrometry

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