Broad Spectrum Bitter Taste Antagonists Discovery

广谱苦味拮抗剂的发现

• 批准号: 10405281
• 负责人: DANIELLE Renee REED
• 金额: $ 2.09万
• 依托单位: DISCOVERYBIOMED, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405281
• 关键词: Address; Affect; Applied Research; Behavior; Beverages; Biological Assay; Businesses; Cell Culture Techniques; Cell Line; Cells; Chemicals; Child; Client; Collaborations; Data; Drug Industry; Elderly; Epithelial Cells; Food; Food Industry; Formulation; Foundations; Funding; Fungiform Papilla; Future; Genetic; Genetic Variation; Genomics; Genotype; Goals; Health; Healthy Eating; Human; Individual; Industry; Industry Collaboration; Institutes; Intellectual Property; International; Joints; Lead; Ligands; Masks; Medicine; Messenger RNA; Methods; Nutritional; Organic Chemicals; Output; Palate; Personal Satisfaction; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Philadelphia; Physiological; Phytochemical; Primary Cell Cultures; Principal Investigator; Proteins; Public Health; Quantitative Reverse Transcriptase PCR; Recommendation; Reporter; Reproducibility; Research; Research Contracts; Research Personnel; Science; Sensory; Signal Transduction; Small Business Technology Transfer Research; Sodium Chloride; Structure-Activity Relationship; Target Populations; Taste Bud Cell; Taste Buds; Taste Perception; Technology; Testing; Tongue; Validation; base; behavior test; cell immortalization; cheminformatics; clinically relevant; compliance behavior; cytotoxicity; design; dietary; drug discovery; ethnic diversity; experimental study; food challenge; food flavor; food insecurity; genetic variant; human subject; improved; innovation; interest; novel; overexpression; programs; public health relevance; receptor; receptor function; reduced food intake; response; salt intake; screening; small molecule; sugar; transcriptome sequencing; validation studies

Principal Investigators for Small Business: DiscoveryBioMed, Inc. (DBM) and Monell Chemical Senses Center Project Summary Abstract Bitter taste in foods and medicines presents a barrier to overcoming global public health challenges: food insecurity, poor nutritional health, and poor compliance with medication use, particularly among children and the elderly. Sugar and salt, the mainstays to address these challenges, further erode nutritional health, and current alternatives have adverse taste attributes of their own. We propose to develop a reliable, human taste- cell screening platform to find bitter blockers of commercial interest to the food, flavor, and pharmaceutical industries, with the ultimate commercial aim to improve the taste and acceptance of nutritious and sustainable foods and medicines. This Phase 2 STTR proposal evolves from a successful Phase 1 STTR funded program to establish primary and immortal human taste-bud-derived epithelial cell cultures and lines (i.e., hTBEC platforms) from donors with bitter-sensitive genotypes and (b) to design, optimize, and implement hTBEC- based bioassays of bitter taste receptor function and other key end points to produce readout data for medium- throughput screening (MTS). Preliminary data is presented in support of the proposed MTS campaign. This Phase 2 STTR proposal seeks to deepen MTS with bitter-responsive hTBEC platforms as the key ingredient. Milestone 1 of the proposal will be underpinned by three specific experimental aims to complete MTS and perform cheminformatics to realize multiple chemical classes that are bitter taste antagonists. Genomic and qRT-PCR analysis of key TAS2R bitter receptors will be performed continually in parallel to insure stability and robustness of the bitter-responsive hTBEC platforms. Milestone 2 of the proposal will identify ‘broad spectrum’ bitter taste antagonists with future marketplace utility and will be underpinned by two specific experimental aims involving secondary validation of bitter taste antagonists in receptor-specific assays, ‘bitterome’ genomics, and human taste behavior. Industry collaborators will test our best candidate bitter taste antagonists independently for rigor and reproducibility against their bitter drugs (e.g., active product ingredients or APIs). Milestone 3 of the proposal will focus on characterizing deeply and selecting the best bitter-responsive hTBEC platforms and bioassays for clients and to optimize and partner bitter taste antagonists with industry to realize new formulations for bitter-tasting drugs and bitter-tasting foods and beverages. This collaboration between DiscoveryBioMed, Inc. and Monell Chemical Senses Center brings together expertise in (a) culture of human taste cells, (b) the creation of immortalized cell lines, (c) MTS, (d) genetics and (e) human sensory analysis. The guiding hypothesis is that hTBEC-platform-based bioassays will provide a more relevant robust way to discover novel ‘bitter blockers’, given the imperfect current methods of overexpressing known taste receptors in heterologous cells. The discovery of bitter taste receptor antagonists that alone or blended together block bitter taste can improve healthy eating by reducing reliance on salt and sugar and can improve compliance by patients taking medicines. Thus, we are confident that new bitter blockers will improve human health. PHS 398/2590 (Rev. 09/04, re-issued 4/2006) Page Continuation Format Page

小型企业的主要调查人员：DiscoveryBioMed，Inc.(DBM)和Monell化学传感中心 项目摘要摘要 食品和药品的苦味是克服全球公共卫生挑战的障碍：食品 不安全、营养健康差和服药依从性差，特别是在儿童和 老年人。糖和盐是应对这些挑战的支柱，进一步侵蚀了营养健康，以及 目前的替代品都有自己不利的品味属性。我们建议开发一种可靠的、人性化的品味- 细胞筛选平台，寻找对食品、香料和药品有商业利益的苦味阻滞剂 行业，最终的商业目标是提高人们对营养和可持续发展的品味和接受度 食物和药品。此第二阶段STTR提案是从第一阶段资助的成功项目演变而来的 建立原代和永生化人类味蕾来源的上皮细胞培养和系(即hTBEC) 平台)和(B)设计、优化和实施hTBEC- 基于苦味感受器功能和其他关键终点的生物测定，以产生读数数据，用于介质- 吞吐量筛选(MTS)。提供了初步数据，以支持拟议的MTS运动。这 第二阶段STTR提案寻求深化MTS，将反应激烈的hTBEC平台作为关键成分。 该提案的里程碑1将由三个具体的实验目标支撑，以完成MTS和 执行化学信息学，以实现多种化学类别的苦味拮抗剂。基因组和 关键的TAS2R苦味受体的QRT-PCR分析将继续并行进行，以确保稳定性和 对苦涩反应敏感的hTBEC平台的健壮性。该提案的里程碑2将确定“广谱” 具有未来市场效用的苦味拮抗剂，并将由两个具体的实验支持 目的是在受体特异性分析中对苦味拮抗剂进行二次验证， 基因组学和人类品味行为。行业合作者将测试我们最好的候选苦味拮抗剂 针对苦味药物(如活性产品成分或原料药)的严密性和重复性。 该提案的里程碑3将侧重于深入描述和选择最具苦味反应的hTBEC 为客户提供平台和生物检测，并优化苦味拮抗剂并与行业合作实现 苦味药物和苦味食品和饮料的新配方。这一合作是 DiscoveryBioMed，Inc.和Monell化学传感中心汇聚了人类文化方面的专业知识 味觉细胞，(B)永生细胞系的建立，(C)MTS，(D)遗传学和(E)人类感官分析。 指导性假设是，基于hTBEC平台的生物检测将提供一种更相关的稳健方法 鉴于目前过度表达已知味觉受体的方法不完善，发现新的“苦味阻滞剂” 在异种细胞中。单独或混合使用苦味受体拮抗剂的发现 苦味可以通过减少对盐和糖的依赖来改善健康饮食，并可以通过以下方式提高遵从性 服药的病人。因此，我们相信，新的苦味阻滞剂将改善人类健康。 PHS 398/2590(09/04版，2006年4月4日重新发布)页面续格式页面

项目成果

Inhibition of Bitter Taste from Oral Tenofovir Alafenamide.

口服替诺福韦艾拉酚胺对苦味的抑制。

• DOI: 10.1124/molpharm.120.000071
• 发表时间: 2021
• 期刊: Molecular pharmacology
• 影响因子: 3.6
• 作者: Schwiebert,Erik;Wang,Yi;Xi,Ranhui;Choma,Katarzyna;Streiff,John;Flammer,LindaJ;Rivers,Natasha;Ozdener,MehmetHakan;Margolskee,RobertF;Christensen,CarolM;Rawson,NancyE;Jiang,Peihua;Breslin,PaulAS
• 通讯作者: Breslin,PaulAS