C3 chemical conjugation to improve the anti-cocaine immune response
C3化学缀合改善抗可卡因免疫反应
基本信息
- 批准号:8233313
- 负责人:
- 金额:$ 28.43万
- 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:2011-03-01 至 2014-02-28
- 项目状态:已结题
- 来源:
- 关键词:Active ImmunizationAdjuvantAffinityAlkynesAntigensAzidesB-Lymphocyte EpitopesBindingChemicalsChemistryCocaineComplementComplexCoupledDevelopmentFemaleHumanImmune responseImmune systemImmunizationImmunoglobulin GKeyhole Limpet HemocyaninLaboratoriesMeasuresMengovirusMethamphetamineMusPharmaceutical PreparationsPhencyclidinePlasmaProcessProteinsResearchScienceSerumSpecificityTechniquesTestingThinkingVaccinesanalogbasechemical synthesiscomparativedesigndrug abuserdrug of abuseimprovednovelprogramspublic health relevanceresearch studysmall moleculevaccine development
项目摘要
DESCRIPTION (provided by applicant): This R21 proposal under PA-10-069 offers to be a leap-forward in immunopharmacotherapy and NIDA's vaccine program for drugs of abuse and 'tests a novel and significant hypothesis which if confirmed by experiment would have a substantial impact on thinking regarding vaccines against small molecules'. The core platform exploits the newly discovered ability to chemically modify complement protein C3 in its native state with functional hydrazide molecules that was made in the PI's research. group to generate revolutionary vaccines based on small molecule drug of abuse molecules as immunogens complexed to C3. The four step theoretical approach to vaccine development is shown in Figure 1. The concept is at once simple, globally applicable and potentially ground breaking. The immunogen is a host protein (not foreign) and should not require an external adjuvant. The development and application of this new immunogen platform will be tested under the remit of the following two aims: Aim 1 Design, synthesis and attachment of linear B-cell epitope-small molecules hydrazides to murine C3 (STEPS 1-3 of Figure 1). The aplication of this new immunopharmacotherapy platform primarily to cocaine (COC), and then to phencyclidine (PCP) and methamphetamine (MET) in mice will be investigated. Thus, mouse C3 (not human) will be isolated and purified for Step 1 of the process using a technique routine in the PI's lab. For Step 2, two hydrazide alkynes, incorporating the Mengo virus VP1259-277 linear B-cell epitope, will be synthesized in the PI's laboratory and these B-cell epitope hydrazide alkynes will be reacted with native murine C3 using conditions already developed in the PI's laboratory. For Step 3, azide analogs of cocaine, PCP and methamphetamine will be synthesized in the PI's laboratory and will be reacted with the C3-alkyne conjugates from Step 2 using standard 'click' chemistry conditions. Aim 2. Active immunization of mice with C3-drug bioconjugates and quantification of the immune response (STEP 4 of Figure 1). The C3-bioconjugates from Aim 1 will be used to immunize female Balb/c mice (3-5 per group), in the presence and absence of external adjuvant (RIBIs). Anti-drug serum titers, polyclonal IgG binding affinity, binding specificity (drug versus B-cell epitope), and IgG persistence all being measured. Comparative immunizations with KLH-conjugates of the drugs will be performed as a control.
PUBLIC HEALTH RELEVANCE: The ability to produce effective vaccines that allow immune system recognition of small molecules is a current unmet need in dug abuse sciences. This proposal harnesses the power of the innate immune system by chemical synthesis of small molecule vaccines coupled to complement protein C3 to generate novel small molecule vaccines.
描述(由申请人提供):PA-10-069下的R21提案是免疫药物治疗和NIDA滥用药物疫苗计划的一个飞跃,并且“测试了一种新的重要假设,如果通过实验证实,将对关于小分子疫苗的思考产生重大影响”。核心平台利用PI研究中新发现的用功能性酰肼分子化学修饰天然状态下补体蛋白C3的能力。该小组将基于小分子药物滥用分子作为与C3复合的免疫原来生产革命性疫苗。疫苗开发的四步理论方法见图1。这一概念既简单,又适用于全球,而且可能具有开创性。免疫原是宿主蛋白(不是外来的),不需要外部佐剂。该新免疫原平台的开发和应用将在以下两个目标的范围内进行测试:目标1线性B细胞表位-小分子酰肼与鼠C3的设计、合成和连接(图1的步骤1-3)。将研究这种新的免疫药物治疗平台在小鼠中主要应用于可卡因(COC),然后应用于苯环己哌啶(PCP)和甲基苯丙胺(MET)。因此,将使用PI实验室的常规技术分离和纯化小鼠C3(非人)用于工艺步骤1。对于步骤2,将在PI的实验室中合成两种酰肼炔(掺入Mengo病毒VP 1259 -277线性B细胞表位),并使用PI实验室中已开发的条件使这些B细胞表位酰肼炔与天然鼠C3反应。对于步骤3,可卡因、PCP和甲基苯丙胺的叠氮化物类似物将在PI的实验室中合成,并将使用标准“点击”化学条件与步骤2的C3-炔缀合物反应。目标二。用C3-药物生物缀合物主动免疫小鼠并定量免疫应答(图1的步骤4)。在存在和不存在外部佐剂(RIBI)的情况下,来自目标1的C3-生物缀合物将用于免疫雌性Balb/c小鼠(每组3-5只)。抗药物血清滴度、多克隆IgG结合亲和力、结合特异性(药物相对于B细胞表位)和IgG持久性都被测量。用药物的KLH-缀合物进行比较性免疫接种作为对照。
公共卫生相关性:生产允许免疫系统识别小分子的有效疫苗的能力是目前药物滥用科学中未满足的需求。该提案通过化学合成与补体蛋白C3偶联的小分子疫苗来利用先天免疫系统的力量,以产生新型小分子疫苗。
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(0)
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 }}
PAUL WENTWORTH其他文献
PAUL WENTWORTH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('PAUL WENTWORTH', 18)}}的其他基金
C3 Tumor Associated Carbohydrate Antigen Bioconjugates
C3 肿瘤相关碳水化合物抗原生物缀合物
- 批准号:
8424948 - 财政年份:2012
- 资助金额:
$ 28.43万 - 项目类别:
C3 Tumor Associated Carbohydrate Antigen Bioconjugates
C3 肿瘤相关碳水化合物抗原生物缀合物
- 批准号:
8301502 - 财政年份:2012
- 资助金额:
$ 28.43万 - 项目类别:
C3 chemical conjugation to improve the anti-cocaine immune response
C3化学缀合改善抗可卡因免疫反应
- 批准号:
8092919 - 财政年份:2011
- 资助金额:
$ 28.43万 - 项目类别:
Lactobacilli surface antibody expression for in vivo protection against cholera
乳酸杆菌表面抗体表达可体内预防霍乱
- 批准号:
7772625 - 财政年份:2010
- 资助金额:
$ 28.43万 - 项目类别:
Lactobacilli surface antibody expression for in vivo protection against cholera
乳酸杆菌表面抗体表达可体内预防霍乱
- 批准号:
8033092 - 财政年份:2010
- 资助金额:
$ 28.43万 - 项目类别:
Beauveriolide-Derived Cyclodepsipeptides as a New Class of Anti-Alzheimer's Drugs
Beauveriolide 衍生的环缩酚肽作为一类新型抗阿尔茨海默病药物
- 批准号:
7758245 - 财政年份:2009
- 资助金额:
$ 28.43万 - 项目类别:
Antibody Generation of ROS and Macular Degeneration
ROS 和黄斑变性的抗体生成
- 批准号:
7273892 - 财政年份:2006
- 资助金额:
$ 28.43万 - 项目类别:
Investigating the link between the atheronals and aging
研究动脉粥样硬化与衰老之间的联系
- 批准号:
7273894 - 财政年份:2006
- 资助金额:
$ 28.43万 - 项目类别:
Investigating the link between the atheronals and aging
研究动脉粥样硬化与衰老之间的联系
- 批准号:
7124089 - 财政年份:2006
- 资助金额:
$ 28.43万 - 项目类别:
Antibody Generation of ROS and Macular Degeneration
ROS 和黄斑变性的抗体生成
- 批准号:
7096710 - 财政年份:2006
- 资助金额:
$ 28.43万 - 项目类别:
相似海外基金
Metachronous synergistic effects of preoperative viral therapy and postoperative adjuvant immunotherapy via long-term antitumor immunity
术前病毒治疗和术后辅助免疫治疗通过长期抗肿瘤免疫产生异时协同效应
- 批准号:
23K08213 - 财政年份:2023
- 资助金额:
$ 28.43万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Improving the therapeutic immunity of cancer vaccine with multi-adjuvant polymeric nanoparticles
多佐剂聚合物纳米粒子提高癌症疫苗的治疗免疫力
- 批准号:
2881726 - 财政年份:2023
- 资助金额:
$ 28.43万 - 项目类别:
Studentship
Evaluation of the Sensitivity to Endocrine Therapy (SET ER/PR) Assay to predict benefit from extended duration of adjuvant endocrine therapy in the NSABP B-42 trial
NSABP B-42 试验中内分泌治疗敏感性 (SET ER/PR) 测定的评估,用于预测延长辅助内分泌治疗持续时间的益处
- 批准号:
10722146 - 财政年份:2023
- 资助金额:
$ 28.43万 - 项目类别:
Countering sympathetic vasoconstriction during skeletal muscle exercise as an adjuvant therapy for DMD
骨骼肌运动期间对抗交感血管收缩作为 DMD 的辅助治疗
- 批准号:
10735090 - 财政年份:2023
- 资助金额:
$ 28.43万 - 项目类别:
AUGMENTING THE QUALITY AND DURATION OF THE IMMUNE RESPONSE WITH A NOVEL TLR2 AGONIST-ALUMINUM COMBINATION ADJUVANT
使用新型 TLR2 激动剂-铝组合佐剂增强免疫反应的质量和持续时间
- 批准号:
10933287 - 财政年份:2023
- 资助金额:
$ 28.43万 - 项目类别:
DEVELOPMENT OF SAS A SYNTHETIC AS01-LIKE ADJUVANT SYSTEM FOR INFLUENZA VACCINES
流感疫苗类 AS01 合成佐剂系统 SAS 的开发
- 批准号:
10935776 - 财政年份:2023
- 资助金额:
$ 28.43万 - 项目类别:
DEVELOPMENT OF SMALL-MOLECULE DUAL ADJUVANT SYSTEM FOR INFLUENZA VIRUS VACCINE
流感病毒疫苗小分子双佐剂体系的研制
- 批准号:
10935796 - 财政年份:2023
- 资助金额:
$ 28.43万 - 项目类别:
A GLYCOLIPID ADJUVANT 7DW8-5 FOR MALARIA VACCINES
用于疟疾疫苗的糖脂佐剂 7DW8-5
- 批准号:
10935775 - 财政年份:2023
- 资助金额:
$ 28.43万 - 项目类别:
Adjuvant strategies for universal and multiseasonal influenza vaccine candidates in the context of pre-existing immunity
在已有免疫力的情况下通用和多季节流感候选疫苗的辅助策略
- 批准号:
10649041 - 财政年份:2023
- 资助金额:
$ 28.43万 - 项目类别:
Adjuvant Photodynamic Therapy to Reduce Bacterial Bioburden in High-Energy Contaminated Open Fractures
辅助光动力疗法可减少高能污染开放性骨折中的细菌生物负载
- 批准号:
10735964 - 财政年份:2023
- 资助金额:
$ 28.43万 - 项目类别: