A platform for therapeutic agents that promote rapid recovery from botulism
促进肉毒杆菌中毒快速康复的治疗剂平台
基本信息
- 批准号:8900900
- 负责人:
- 金额:$ 85.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-09-01 至 2017-08-31
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAnimal TestingAnimalsAntidotesBindingBloodBontoxilysinBotulinum Toxin Type ABotulismCategoriesCellsCenters for Disease Control and Prevention (U.S.)Clostridium botulinumClostridium difficileCytosolDevelopmentDoseDrug KineticsDrug TargetingEngineeringEvaluationExposure toF Box DomainHandIntoxicationLeadMeasuresMedicalModelingModificationMolecularMusMuscle functionNatureNeuronsOryctolagus cuniculusParalysedPatientsPeptide HydrolasesPharmaceutical PreparationsProteinsRecombinantsRecoveryResearchRiskRouteSNAP receptorSafetySerotypingSerumSpecificitySystemTestingTherapeuticTherapeutic AgentsTherapeutic Human ExperimentationToxic effectToxinbasebiodefensebotulinum toxin type Bbotulinum toxin type Cdesigndrug developmentenzyme activityenzyme substrateinnovationmotor function recoverymutantnanobodiesneurotransmitter releasenovel therapeuticspolypeptidepre-clinicalprogramspublic health relevancereceptorresearch clinical testingrestorationsafety testingsmall moleculeubiquitin-protein ligase
项目摘要
DESCRIPTION (provided by applicant): Botulism is caused by exposure to toxins produced by Clostridium botulinum neurotoxin (BoNT), a CDC Category A biodefense threat agent for which no antidote currently exists. Seven different BoNT serotypes have been discovered to date (BoNT/A-G), many having numerous additional BoNT subtypes. To protect against all of these diverse BoNT bioterror threats, expensive conventional small molecule drug development would need to be separately performed for each of the seven different drug targets and perhaps others. This challenge, together with other extreme hurdles confronting BoNT small molecule drug development, particularly complicates efforts to develop small molecule drugs to treat botulism. New therapeutic paradigms are urgently needed to counter the enormous risks associated with these easy to obtain, easy to produce and extremely dangerous bioterror agents. We have developed and then extensively optimized two distinct 'designer E3-ligase' agents that each accelerate the 'molecular cure' of neurons intoxicated by one of the two most dangerous Botulinum neurotoxins, serotypes A or B (BoNT/A, BoNT/B). These two lead agents consist of the F-box domain of TrCP fused to a camelid 'nanobody' domain with binding specificity for one of the BoNT proteases. These polypeptide agents, with a size less than 30 kDa, bind to the BoNT protease and cause its rapid, intraneuronal destruction leading to rapid recovery of the neuron. Because of the modular nature of this antidote, it will be simple and straightforward to develop similar agents to treat all other BoNT serotypes and subtypes simply by substituting the nanobody domains with another having the appropriate specificity. In this proposal, we will develop a general delivery vehicle to deliver our two lead agents to the cytosol of intoxicated neurons within botulism patients and perform pre-clinical evaluation. As the vehicle, we propose to use an atoxic Clostridial toxin-based neuronal delivery vehicle (TNDV) due to its highly evolved capability to enter the body, survive in serum and deliver enzyme activities to the cytosol of targeted cells. We will develop three different and proven TNDV systems, each having unique and compelling features, and then select the best vehicle(s) for further development and animal testing. The three TNDV systems will be modified, atoxic forms of: 1) BoNT serotype C; 2) C. difficile toxin B and; 3) Clostridial C2 toxin. If successful, it is expected that similar agents could be developed to target the accelerated turnover of virtually any cytosolic neuronal protein for research or therapeutic applications.
描述(由申请人提供):肉毒杆菌中毒是由接触肉毒梭菌神经毒素(BoNT)产生的毒素引起的,BoNT是CDC的a类生物防御威胁剂,目前没有解药。迄今为止,已经发现了7种不同的BoNT血清型(BoNT/A-G),其中许多有许多附加的BoNT亚型。为了防止所有这些不同的BoNT生物恐怖威胁,昂贵的传统小分子药物开发需要分别针对七种不同的药物靶标进行,也许还有其他靶标。这一挑战,加上BoNT小分子药物开发面临的其他极端障碍,使开发治疗肉毒杆菌中毒的小分子药物的努力变得尤其复杂。迫切需要新的治疗范例来应对与这些容易获得、容易生产和极其危险的生物恐怖制剂相关的巨大风险。我们已经开发并广泛优化了两种不同的“设计e3连接酶”制剂,每种制剂都可以加速被两种最危险的肉毒杆菌神经毒素之一(血清型A或B) (BoNT/A, BoNT/B)中毒的神经元的“分子治疗”。这两种先导药物由TrCP的F-box结构域与具有BoNT蛋白酶结合特异性的骆驼“纳米体”结构域融合而成。这些多肽制剂的大小小于30kda,与BoNT蛋白酶结合,导致其在神经元内的快速破坏,从而导致神经元的快速恢复。由于这种解毒剂的模块化性质,开发类似的药物来治疗所有其他BoNT血清型和亚型,只需用另一个具有适当特异性的纳米体结构域替代这些纳米体结构域,就会变得简单直接。在本提案中,我们将开发一种通用的递送载体,将我们的两种先导药物递送到肉毒中毒患者的中毒神经元的细胞质中,并进行临床前评估。作为载体,我们建议使用一种有毒的基于梭状芽胞杆菌毒素的神经元递送载体(TNDV),因为它具有高度进化的能力,可以进入体内,在血清中存活,并将酶活性传递到目标细胞的细胞质中。我们将开发三种不同且经过验证的TNDV系统,每种系统都具有独特而引人注目的功能,然后选择最佳车辆进行进一步开发和动物试验。三种TNDV系统将被修改,毒性形式:1)BoNT血清型C;2) C.艰难梭菌毒素B和;3) C2梭菌毒素。如果成功,预计类似的药物可以开发针对几乎任何细胞胞质神经元蛋白的加速周转的研究或治疗应用。
项目成果
期刊论文数量(0)
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George A. Oyler其他文献
George A. Oyler的其他文献
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{{ truncateString('George A. Oyler', 18)}}的其他基金
A platform for therapeutic agents that promote rapid recovery from botulism
促进肉毒杆菌中毒快速康复的治疗剂平台
- 批准号:
8711231 - 财政年份:2011
- 资助金额:
$ 85.96万 - 项目类别:
A platform for therapeutic agents that promote rapid recovery from botulism
促进肉毒杆菌中毒快速康复的治疗剂平台
- 批准号:
8076439 - 财政年份:2011
- 资助金额:
$ 85.96万 - 项目类别:
A platform for therapeutic agents that promote rapid recovery from botulism
促进肉毒杆菌中毒快速康复的治疗剂平台
- 批准号:
8523772 - 财政年份:2011
- 资助金额:
$ 85.96万 - 项目类别:
A platform for therapeutic agents that promote rapid recovery from botulism
促进肉毒杆菌中毒快速康复的治疗剂平台
- 批准号:
8323222 - 财政年份:2011
- 资助金额:
$ 85.96万 - 项目类别:
High Throughput Screens for Botulinum Toxin Therapeutics
肉毒毒素治疗的高通量筛选
- 批准号:
7020809 - 财政年份:2005
- 资助金额:
$ 85.96万 - 项目类别:
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