Broad Spectrum Bitter Taste Antagonists Discovery

广谱苦味拮抗剂的发现

基本信息

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
项目类别：
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

项目摘要

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

小型企业的主要研究人员：DiscoveryBiomed，Inc。（DBM）和Monell Chemical Senses Center 项目摘要摘要食物和药品中的苦味呈现出克服全球公共卫生挑战的障碍：食物不安全感，营养健康不良以及对药物使用的依从性不佳，尤其是在儿童中较早的。糖和盐，解决这些挑战的主要支柱，进一步侵蚀营养健康，当前的替代品具有自己的不良口味属性。我们建议发展一种可靠的人类品味 - 细胞筛选平台，以找到食物，风味和药品的商业兴趣的苦封码器行业，最终的商业目的是改善营养和可持续性的口味和接受食物和药物。该阶段2 STTR提案从成功的1阶段STTR资助计划中的演变建立原发性和不朽的人类味道衍生的上皮细胞培养和线条（即HTBEC 平台）来自具有痛苦基因型的捐助者以及（b）设计，优化和实施HTBEC- 基于苦味受体功能和其他关键终点的基于生物测定，以生成中等的读数数据吞吐量筛选（MTS）。初步数据是为了支持拟议的MTS活动。这第2阶段的STTR提案旨在以苦难的HTBEC平台作为关键成分来加深MTS。该提案的里程碑1将以三个特定的实验目标为基础，以完成MTS和执行化学信息学以实现多个苦味拮抗剂的化学类别。基因组和 QRT-PCR分析键Tas2r苦接收器将与确保稳定性并行进行连续执行痛苦的HTBEC平台的鲁棒性。该提案的里程碑2将确定“广泛范围” 具有未来市场公用事业的苦味拮抗剂，将受到两个特定的实验的支持在特定于接收器的测定中涉及苦味拮抗剂的次要验证的目的，“ bitterome” 基因组学和人类味道行为。行业合作者将测试我们最好的候选人苦味对手独立于针对其苦药（例如，活性产品成分或API）的严格性和可重复性。该提案的里程碑3将重点介绍并选择最佳的痛苦htbec 为客户提供平台和生物测定苦味药物和苦味的食物和卧室的新配方。这之间的合作 DiscoveryBiomed，Inc。和Monell Chemical Senses Center汇集了（a）人类文化的专业知识味道细胞，（b）产生永生的细胞系，（c）mts，（d）遗传学和（e）人类感觉分析。指导假设是，基于HTBEC-PLATFORM的生物测定将提供更相关的强大方法考虑到过表达已知味觉受体的当前方法，发现新颖的“苦被阻滞剂” 在异源细胞中。发现单独或混合在一起的苦味受体拮抗剂的发现苦味可以通过减轻盐和糖的释放来改善健康饮食，并通过服用药物的患者。这是我们有信心的，新的苦难者将改善人类健康。 PHS 398/2590（修订版09/04，重新发布4/2006）页面延续格式页面

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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