Development of Long-acting Cocaine Hydrolase as a Treatment for Cocaine Abuse
开发长效可卡因水解酶来治疗可卡因滥用
基本信息
- 批准号:9754089
- 负责人:
- 金额:$ 81.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-15 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAlbuminsAnimal ModelAnimalsAntibodiesBindingBinding SitesBiologicalBiological AssayButyrylcholinesteraseCell LineClinical DataClinical TrialsCocaineCocaine AbuseCocaine DependenceCommunitiesComputer SimulationDataDevelopmentDoseDrug KineticsEnzymesEvaluationFDA approvedFamilyFormulationHalf-LifeHumanHydrolaseHydrolysisImmunoglobulinsIn VitroInjectionsInvestigationInvestigational DrugsLegal patentMedicalMetabolicMetabolismMonkeysMonoclonal AntibodiesNeuraxisNeuronsPathway interactionsPharmaceutical PreparationsPharmacodynamicsPharmacology and ToxicologyPlasmaPreclinical TestingProcessProductionProteinsPublic HealthRattusRouteSelf AdministrationSerum AlbuminTechnologyTestingToxic effectTreatment ProtocolsVaccinesWorkbasecell bankclinical developmentcocaine overdosedesigndrug of abuseenzyme therapyexpression cloningimmunogenicityimprovedin vivoinnovationmanufacturing processmanufacturing process developmentmutantnovelnovel therapeuticsoff-patentpublic health relevancesmall moleculesocialsuccesstherapeutic candidatetreatment strategy
项目摘要
DESCRIPTION (provided by applicant): Cocaine abuse is a major public health problem that directly or indirectly affects most communities and families. There is still no FDA-approved medication specific for cocaine addiction or overdose. Disastrous medical and social consequences of cocaine abuse have made the development of an anti-cocaine medication a high priority. Accelerating cocaine metabolism that produces biologically inactive metabolites via a route similar to the principal cocaine-metabolizing pathway-cocaine hydrolysis catalyzed by human butyrylcholinesterase (BChE) in plasma-is recognized as the most efficient treatment strategy for cocaine overdose and addiction. Since the catalytic efficiency (kcat/KM) of wild-type BChE against the naturally occurring (-)-cocaine is low (kcat = 4.1 min and KM = 4.5 µM), we have recently designed and discovered a set of BChE -1 mutants, known as cocaine hydrolases (CocHs), with at least 1,000-fold improved catalytic efficiency against (- )-cocaine compared to wild-type BChE. In vivo and clinical data for the first one of our discovered and patented CocHs demonstrate the promise of enzyme therapy for cocaine abuse. In addition to improved efficacy, our recently designed, discovered, and patented new CocH entities have not only significantly higher catalytic efficiency against (-)-cocaine, but also possess much longer biological half-lives Built on our success in rational design and discovery of the highly efficient CocHs and their long-acting forms (LAFs or CocH-LAFs), this investigation will focus on further optimization, manufacturing process development, formulation development, and preclinical testing of the most promising CocH-LAF as a novel therapeutic candidate for cocaine addiction treatment. The specific aims are: (1) to optimize a promising CocH-LAF which has not only a high catalytic efficiency against (-)-cocaine, but also a long biological half-life; (2) to test feasibility of lage- scale expression of promising CocH-LAF entities; (3) to develop large-scale manufacturing processes for the most promising CocH-LAF selected in Aim 2; (4) to characterize the detailed pharmacology and toxicology profiles of the most promising CocH-LAF in animal models with the CocH-LAF material produced in Aim 3. The most promising CocH-LAF entity developed in this investigation is expected to be highly effective and safe as a novel exogenous enzyme suitable for a monthly dosing schedule for treatment of cocaine addiction in humans. This investigation will make the best possible CocH-LAF entity ready for the cGMP (current Good Manufacturing Practices) protein manufacturing, Investigational New Drug (IND)-enabling studies, and subsequent clinical trials. Thus, this investigation will move a promising therapeutic
candidate closer toward FDA approval for cocaine addiction treatment.
描述(由申请人提供): 可卡因滥用是一个直接或间接影响大多数社区和家庭的重大公共卫生问题 目前尚无 FDA 批准的专门用于治疗可卡因成瘾或过量服用的药物。开发抗可卡因药物是当务之急,加速可卡因代谢,通过类似于人类催化的主要可卡因代谢途径(可卡因水解)的途径产生无生物活性的代谢物。血浆中的丁酰胆碱酯酶 (BChE) 被认为是治疗可卡因过量和成瘾的最有效的治疗策略,因为野生型 BChE 对天然存在的 (-)-可卡因的催化效率 (kcat/KM) 较低(kcat = 4.1)。 min 和 KM = 4.5 µM),我们最近设计并发现了一组 BChE -1 突变体,称为可卡因水解酶 (CocHs),至少具有与野生型 BChE 相比,我们发现的第一个获得专利的 CocH 的催化效率提高了 1,000 倍,这证明了酶疗法治疗可卡因滥用的前景。我们最近设计、发现并获得专利的新 CocH 实体不仅对 (-)-可卡因具有显着更高的催化效率,而且还具有更长的生物半衰期 基于我们在合理设计和发现方面的成功高效 CocH 及其长效形式(LAF 或 CocH-LAF)的研究,本研究将重点关注最有前途的 CocH-LAF 作为新型治疗候选药物的进一步优化、制造工艺开发、制剂开发和临床前测试。具体目标是:(1)优化一种有前景的CocH-LAF,它不仅对(-)-可卡因具有高催化效率,而且具有长的生物半衰期; (2) 测试大规模表达有前景的 CocH-LAF 实体的可行性; (3) 为目标 2 中选择的最有前途的 CocH-LAF 开发大规模生产工艺; (4) 表征详细的药理学和毒理学;使用目标 3 中生产的 CocH-LAF 材料在动物模型中对最有前途的 CocH-LAF 进行分析。本次研究中开发的最有前途的 CocH-LAF 实体预计将作为一种新型外源性高效且安全的实体适合用于治疗人类可卡因成瘾的每月给药方案的酶 这项研究将使最好的 CocH-LAF 实体为 cGMP(现行良好生产规范)蛋白质生产、研究性新药 (IND) 支持研究和研究做好准备。因此,这项研究将推动一种有前途的治疗方法。
候选人更接近 FDA 批准可卡因成瘾治疗。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
CHANG-GUO ZHAN其他文献
CHANG-GUO ZHAN的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('CHANG-GUO ZHAN', 18)}}的其他基金
Effects of HIV-1 Tat protein and methamphetamine on VMAT2-mediated dopamine transmission in the context of neuroHIV and drug abuse
HIV-1 Tat 蛋白和甲基苯丙胺对神经 HIV 和药物滥用背景下 VMAT2 介导的多巴胺传递的影响
- 批准号:
10698618 - 财政年份:2023
- 资助金额:
$ 81.18万 - 项目类别:
Long-acting aldicarb hydrolase as a medical countermeasure for aldicarb poisoning
长效涕灭威水解酶作为涕灭威中毒的医学对策
- 批准号:
10724752 - 财政年份:2023
- 资助金额:
$ 81.18万 - 项目类别:
Ghrelin Deacylase as a Treatment for Opioid Polysubstance Abuse
生长素释放肽脱酰酶治疗阿片类多物质滥用
- 批准号:
10510245 - 财政年份:2022
- 资助金额:
$ 81.18万 - 项目类别:
Development of a Long-acting Enzyme Therapy for Treatment of Cocaine Abuse
开发治疗可卡因滥用的长效酶疗法
- 批准号:
10405101 - 财政年份:2020
- 资助金额:
$ 81.18万 - 项目类别:
Development of a Long-acting Enzyme Therapy for Treatment of Cocaine Abuse
开发治疗可卡因滥用的长效酶疗法
- 批准号:
10231091 - 财政年份:2020
- 资助金额:
$ 81.18万 - 项目类别:
Development of Long-acting Cocaine Hydrolase as a Treatment for Cocaine Abuse
开发长效可卡因水解酶来治疗可卡因滥用
- 批准号:
9139953 - 财政年份:2015
- 资助金额:
$ 81.18万 - 项目类别:
Long-lasting cocaine-metabolizing enzyme for cocaine addiction treatment
用于可卡因成瘾治疗的长效可卡因代谢酶
- 批准号:
8636423 - 财政年份:2013
- 资助金额:
$ 81.18万 - 项目类别:
相似国自然基金
α-乳白蛋白姜黄素纳米复合物通过PepT1-溶酶体提高生物利用度对镉致动脉粥样硬化的干预作用机制研究
- 批准号:82373600
- 批准年份:2023
- 资助金额:49 万元
- 项目类别:面上项目
用于胰腺癌光免疫协同治疗的单分子白蛋白纳米粒及其增敏机制研究
- 批准号:32330060
- 批准年份:2023
- 资助金额:212 万元
- 项目类别:重点项目
大豆肽调控白蛋白程序化代谢的吸收界面及构效机制研究
- 批准号:32372317
- 批准年份:2023
- 资助金额:50 万元
- 项目类别:面上项目
小白蛋白调控巨噬细胞极化改善泌乳素瘤耐药的机制研究
- 批准号:82373131
- 批准年份:2023
- 资助金额:48 万元
- 项目类别:面上项目
巯基介导的花色苷/豌豆白蛋白递送体系与肠道粘蛋白MUC2的粘附作用机制研究
- 批准号:32372360
- 批准年份:2023
- 资助金额:50 万元
- 项目类别:面上项目
相似海外基金
Novel therapies for obesity- or diabetes-related lymphatic dysfunction
肥胖或糖尿病相关淋巴功能障碍的新疗法
- 批准号:
10602589 - 财政年份:2023
- 资助金额:
$ 81.18万 - 项目类别:
Evaluation of New Anti-inflammatory Treatments for Age-Related Macular Degeneration
年龄相关性黄斑变性的新型抗炎治疗方法的评价
- 批准号:
10642988 - 财政年份:2023
- 资助金额:
$ 81.18万 - 项目类别:
Overcoming pressure ulcers with engineered hormones and stem cells
用工程激素和干细胞克服压疮
- 批准号:
10821146 - 财政年份:2023
- 资助金额:
$ 81.18万 - 项目类别:
MRI-Based Renal Oximetry in Early Diabetic Kidney Disease
基于 MRI 的肾血氧饱和度在早期糖尿病肾病中的应用
- 批准号:
10593684 - 财政年份:2023
- 资助金额:
$ 81.18万 - 项目类别:
Using human liver tissue equivalents to optimize AAV-mediated GT and better define age-related clinical risks
使用人类肝脏组织等效物优化 AAV 介导的 GT 并更好地定义与年龄相关的临床风险
- 批准号:
10567919 - 财政年份:2023
- 资助金额:
$ 81.18万 - 项目类别: