Development of taste receptor ligands using structure-activity studies

描述(申请人提供)：作为动物检测营养丰富的食物和辨别毒素的主要机制，味觉对健康和行为有重大影响。苦味具有高度的敏感性和广泛的特异性，可以引起强烈的厌恶反应，影响与健康相关的行为，如饮食偏好和药物依从性。相反，甜味有助于检测和摄入高碳水化合物(因此也就是高热量)食物，但过度摄入卡路里可能导致肥胖和糖尿病。因此，在许多情况下需要操纵味觉和/或提供味觉替代品。苦味、甜味和鲜味(可口)是由属于G蛋白偶联受体(GPCR超家族)的一组味觉受体(TASR)在细胞水平上检测到的。由于它们难以直接进行结构可视化，如X射线结晶学，因此人们对负责结合配体的TASR的结构特征知之甚少。阐明TASR-配体的结构相互作用有助于开发与健康相关的产品，如苦味阻滞剂和糖替代品。这一提议的结果将使能够开发TASR的配体，并可能开发其他GPCR。与公共健康相关：味觉配体目前被用来掩盖令人厌恶的味道，提高患者的依从性，影响食物的选择，并改变卡路里摄入量，因此经常影响人类的日常活动。这一提议将通过利用研究平台发现新的味觉配体，为人类健康做出贡献。

DESCRIPTION (provided by applicant): As the primary mechanism by which animals detect nutrient-rich foods and discriminate against toxins, the sense of taste has a significant impact on health and behavior. Bitter tastes are perceived with high sensitivity and broad specificity, and can evoke strong aversive reactions that influence health-related behaviors such as dietary preference and pharmaceutical compliance. Conversely, sweet taste facilitates the detection and consumption of high carbohydrate (and hence highly caloric) foods, but over-consumption of calories can lead to obesity and diabetes. It is therefore desirable in many circumstances to manipulate taste perception and/or to provide taste substitutes. Bitter, sweet, and umami (savory) tastes are detected at the cellular level by a family of taste receptors (TASRs), which belong to the G protein-coupled receptor (GPCR) superfamily of proteins. Because they are refractory to direct structural visualization such as x-ray crystallography, very little is known about the structural features of TASRs that are responsible for binding ligands. Elucidating TASR-ligand structural interactions could enable the development of health-related products, such as bitter blockers and sugar substitutes. The results of this proposal would enable ligands of TASRs, and possibly other GPCRs, to be developed. PUBLIC HEALTH RELEVANCE: Taste ligands are currently used to mask aversive tastes, improve patient compliance, influence choice of foods, and modify caloric intake, so routinely influence daily human activity. This proposal will contribute to human health by using a research platform to discover novel taste ligands.