Catalytic bioscavengers as countermeasures against organophosphate nerve agents

Goldsmith, Moshe; Ashani, Yacov

doi:10.1016/j.cbi.2018.07.006

Cited by 42 publications

(26 citation statements)

References 247 publications

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“…These findings led to the hypothesis that BuChE might be developed as an effective nerve agent MCM that would confer a similar protective effect against nerve agent exposure in the average human -effectively conferring a super-detoxification ability to the recipient. This hypothesis is supported by extensive research and clinical trials undertaken to develop a operationalised MCM (14,16,18,19,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). The human BuChE gene has also recently been incorporated into a bacterial host, for the purpose of large scale production of therapeutic BuChE.…”

Section: Enhancing Innate Resilience Of Soldiers To Nerve Agents and mentioning

confidence: 98%

Beyond traditional CBRN force protection – a future of CBRN hardened super-soldiers?

Heslop

2019

Global Biosecurity

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Current momentum in military research efforts has opened the possibility for the enhancement, but also augmentation of military personnel for the purpose of achieving advantage over rivals. Rapid technological advances are currently breaking ground well ahead of prudent commentary and consideration of impacts on human society, ethics, geopolitics and military operations. This has potentially allowed friend and foe alike to exploit opportunities to develop completely novel countermeasures and defences and develop new threats in Chemical, Biological, Radiological and Nuclear (CBRN) military operations. In this editorial, two recent technological developments driving medical countermeasure research are highlighted as examples. How such developments impact on capability competitions-in other words, driving new arms races-in near-peer rivals is discussed. The profound potential impacts of these new technologies on the fundamentals of human existence as we understand it today are highlighted. How to cite this article: Heslop DJ. Beyond traditional CBRN force protection-a future of CBRN hardened super-soldiers? Global Biosecurity, 2019; 1(1).

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Section: Enhancing Innate Resilience Of Soldiers To Nerve Agents and mentioning

confidence: 98%

Beyond traditional CBRN force protection – a future of CBRN hardened super-soldiers?

Heslop

2019

Global Biosecurity

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“…26 It has been suggested that in order for the enzyme to be used as a biotherapeutic, its efficacy should be on the order of 10 7 . 26 Thus, enzyme engineering efforts have been primarily targeted toward increasing the catalytic efficiency of PTE against other substrates, specifically the more toxic S P enantiomers of nerve agents due to PTE naturally preferring the less toxic R P enantiomer. 3…”

Section: Genetic Engineering Of Ptementioning

confidence: 99%

“…24 Native PTE has been found to break down a number of OPs and has been the subject of engineering efforts to improve its performance. 3 PTE was found to protect mice from multiple lethal doses (4-7 × LD 50 ) of paraoxon, diethylfluorophosphate (DFP), and GA. 26 Thus, engineering an improved PTE has significant potential in biomedical, environmental, and homeland defense applications. In this review, we discuss recent developments in the genetic and form factor (i.e., physical and chemical modifications to PTE postexpression) engineering efforts.…”

Section: Introductionmentioning

confidence: 99%

Enhancing organophosphate hydrolase efficacy via protein engineering and immobilization strategies

Katyal

Chu

Montclare

2020

Annals of the New York Academy of Sciences

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Organophosphorus compounds (OPs), developed as pesticides and chemical warfare agents, are extremely toxic chemicals that pose a public health risk. Of the different detoxification strategies, organophosphate-hydrolyzing enzymes have attracted much attention, providing a potential route for detoxifying those exposed to OPs. Phosphotriesterase (PTE), also known as organophosphate hydrolase (OPH), is one such enzyme that has been extensively studied as a catalytic bioscavenger. In this review, we will discuss the protein engineering of PTE aimed toward improving the activity and stability of the enzyme. In order to make enzyme utilization in OP detoxification more favorable, enzyme immobilization provides an effective means to increase enzyme activity and stability. Here, we present several such strategies that enhance the storage and operational stability of PTE/OPH.

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“…OP hydrolases are of great biotechnological and medical interest. Phosphotriesterases (PTE) of various origins, in particular, can be used for detection of OPs [13], decontamination and remediation [8,[14][15][16][17][18] and for therapy of OP poisoning as catalytic bioscavengers [7,[19][20][21][22]. Because OPs are hemi-substrates of ChEs, research of novel human ChE mutants capable of hydrolyzing OPs is of great interest for improving catalytic bioscavenger-based medical countermeasures of OP poisoning [23][24][25] and implementation of pseudocatalytic bioscavenger systems composed of ChE-reactivator [26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Steady-State Kinetics of Enzyme-Catalyzed Hydrolysis of Echothiophate, a P–S Bonded Organophosphorus as Monitored by Spectrofluorimetry

et al. 2020

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Enzyme-catalyzed hydrolysis of echothiophate, a P–S bonded organophosphorus (OP) model, was spectrofluorimetrically monitored, using Calbiochem Probe IV as the thiol reagent. OP hydrolases were: the G117H mutant of human butyrylcholinesterase capable of hydrolyzing OPs, and a multiple mutant of Brevundimonas diminuta phosphotriesterase, GG1, designed to hydrolyze a large spectrum of OPs at high rate, including V agents. Molecular modeling of interaction between Probe IV and OP hydrolases (G117H butyrylcholinesterase, GG1, wild types of Brevundimonas diminuta and Sulfolobus solfataricus phosphotriesterases, and human paraoxonase-1) was performed. The high sensitivity of the method allowed steady-state kinetic analysis of echothiophate hydrolysis by highly purified G117H butyrylcholinesterase concentration as low as 0.85 nM. Hydrolysis was michaelian with Km = 0.20 ± 0.03 mM and kcat = 5.4 ± 1.6 min−1. The GG1 phosphotriesterase hydrolyzed echothiophate with a high efficiency (Km = 2.6 ± 0.2 mM; kcat = 53400 min−1). With a kcat/Km = (2.6 ± 1.6) × 107 M−1min−1, GG1 fulfills the required condition of potential catalytic bioscavengers. quantum mechanics/molecular mechanics (QM/MM) and molecular docking indicate that Probe IV does not interact significantly with the selected phosphotriesterases. Moreover, results on G117H mutant show that Probe IV does not inhibit butyrylcholinesterase. Therefore, Probe IV can be recommended for monitoring hydrolysis of P–S bonded OPs by thiol-free OP hydrolases.

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Catalytic bioscavengers as countermeasures against organophosphate nerve agents

Cited by 42 publications

References 247 publications

Beyond traditional CBRN force protection – a future of CBRN hardened super-soldiers?

Beyond traditional CBRN force protection – a future of CBRN hardened super-soldiers?

Enhancing organophosphate hydrolase efficacy via protein engineering and immobilization strategies

Steady-State Kinetics of Enzyme-Catalyzed Hydrolysis of Echothiophate, a P–S Bonded Organophosphorus as Monitored by Spectrofluorimetry

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