Refined uncharged Bis-Oximes for Rapid CNS Reactivation of OP-Inhibited hAChE.
Refined uncharged Bis-Oximes for Rapid CNS Reactivation of OP-Inhibited hAChE.
批准号:
10407766
负责人:
Zoran Radic
金额:
$24.69万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-04-01 至 2024-03-31
关键词:
AcetylcholinesteraseAcheAddressAntidotesBlood - brain barrier anatomyChemical WeaponsComplexDataDevelopmentDoseEvaluationGenerationsHumanIn VitroIndividualIntoxicationMolecular ConformationMusNeuraxisNeutronsOrganophosphatesOximesOxygenParaoxonPeripheralPesticidesPhosphorusRecoveryReportingRoentgen RaysSarinSecuritySerineStructureTestingTissuesTreatment Efficacyarmbaseblood-brain barrier penetrationcyclic aminecyclosarindesignefficacy testingflexibilityimprovedin vitro testingin vivonerve agentnonhuman primatenovelpesticide exposurephosphoramidatepreventscaffoldvibration
中文摘要
精制的不带电双肟用于op抑制hAChE的快速中枢神经系统再激活。
英文摘要
Refined uncharged bis-oximes for rapid CNS reactivation of OP-inhibited hAChE.
Project Summary. Reactivation of organophosphate (OP) inhibited acetylcholinesterase
(AChE) by anti-OP antidotes is the only true remedy for OP intoxication in nerve agent or OP
pesticide exposure. Most of currently approved and experimental anti-OP antidotes are
nucleophilic aldoximes that attack and remove phosphorus atom of OPs covalently attached to
the AChE active serine.
One significant way of improving current antidotal treatment of OP intoxication is by creation
of reactivating antidotes that will reach inhibited AChE in peripheral tissue but also in the CNS,
where currently approved antidotes cannot enter.
We have designed and characterized in vitro seven improved uncharged LG bis-oxime
antidotes of a novel scaffold, with better reactivation of sarin, cyclosarin, VX and paraoxon
inhibited hAChE than RS194B.
The uniquely novel feature of the LG bis-oxime scaffold is that ionizable cyclic amines and
aldoxime groups allow single compound to equilibrate between up to sixteen ionic forms differing
in nucleophilic reactivity and in conformation.
We now propose to explore and structurally optimize this new antidote scaffold, based on our
yet unpublished X-ray structural templates of both LG bis-oximes and of the fastest pyridinium
bis-oxime MMB4. Templates will be informed by inelastic neutron scattering (INS) data. We will
test refined compounds for reactivation potency against OP-hAChE conjugates in vitro and will
evaluate the initial PK profile of most promissing reactivators in mice. Interaction of best refined
candidates with AChE will be explored by X-ray and INS.
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会议论文
In Vivo Efficacy of Novel Uncharged Bis-Oximes in OP Poisoning Treatment
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批准号:10412696
-
项目类别:
-
资助金额:$20.98万
-
财政年份:2022
-
负责人:Zoran Radic
-
依托单位:
Refined uncharged Bis-Oximes for Rapid CNS Reactivation of OP-Inhibited hAChE.
-
批准号:10582723
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项目类别:
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资助金额:$19.27万
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财政年份:2022
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负责人:Zoran Radic
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依托单位:
In Vivo Efficacy of Novel Uncharged Bis-Oximes in OP Poisoning Treatment
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批准号:10598635
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项目类别:
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资助金额:$15.58万
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依托单位:
Overlay independent X-ray data analysis for enhanced oxime OP-ChE reactivation
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批准号:9356345
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Overlay independent X-ray data analysis for enhanced oxime OP-ChE reactivation
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项目类别:
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Accelerated AChE Reactivator Design by Mechanistic Neutron Scattering Studies
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依托单位:
Accelerated AChE Reactivator Design by Mechanistic Neutron Scattering Studies
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批准号:9632884
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依托单位:
Accelerated AChE Reactivator Design by Mechanistic Neutron Scattering Studies
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批准号:8892277
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项目类别:
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资助金额:$67.02万
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财政年份:2014
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负责人:Zoran Radic
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依托单位:
BChE reactivators for nerve agent and pesticide OP detoxification in human tissue
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批准号:8610134
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项目类别:
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资助金额:$41.27万
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财政年份:2013
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负责人:Zoran Radic
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依托单位:
BChE reactivators for nerve agent and pesticide OP detoxification in human tissue
-
批准号:8738731
-
项目类别:
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资助金额:$38.52万
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财政年份:2013
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负责人:Zoran Radic
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依托单位:
Optimization of nonpyridinium oximes for BChE hydrolysis of OPs in plasma
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批准号:8020885
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项目类别:
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资助金额:$41.58万
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负责人:Zoran Radic
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依托单位:
Optimization of nonpyridinium oximes for BChE hydrolysis of OPs in plasma
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批准号:8153134
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项目类别:
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资助金额:$41.38万
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财政年份:2010
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负责人:Zoran Radic
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依托单位:
Optimization of nonpyridinium oximes for BChE hydrolysis of OPs in plasma
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批准号:8508593
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项目类别:
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资助金额:$7.75万
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财政年份:2010
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负责人:Zoran Radic
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依托单位:
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