Modulation of bitter taste perception by a small molecule hTAS2R antagonist.
Modulation of bitter taste perception by a small molecule hTAS2R antagonist.
复制标题
DOI：
10.1016/j.cub.2010.04.043
复制
发表时间：
2010-06-22
期刊：
影响因子：
9.2
通讯作者：
Meyerhof, Wolfgang
中科院分区：
文献类型：
--
作者：
Slack, Jay P.;Brockhoff, Anne;Batram, Claudia;Menzel, Susann;Sonnabend, Caroline;Born, Stephan;Galindo, Maria Mercedes;Kohl, Susann;Thalmann, Sophie;Ostopovici-Halip, Liliana;Simons, Christopher T.;Ungureanu, Ioana;Duineveld, Kees;Bologa, Cristian G.;Behrens, Maik;Furrer, Stefan;Oprea, Tudor I.;Meyerhof, Wolfgang
人类的苦味是由 G 蛋白偶联受体 hTAS2R 家族介导的。 hTAS2Rs 的发现使得开发特异性苦味受体拮抗剂成为可能，这些拮抗剂可作为化学探针来检查苦味受体功能在味觉和非味觉组织中的作用。此外，它们可以广泛应用于添加维生素、抗氧化剂和其他营养保健品的食品和饮料中，因为其中许多都有令人讨厌的苦味余味。我们采用高通量筛选方法发现了一种新型苦味受体拮抗剂 (GIV3727)，它可以抑制糖精和安赛蜜（两种常见的人工甜味剂）对 hTAS2R31 的激活。药理学分析表明，GIV3727 可能充当 hTAS2R31 的正位、不可克服的拮抗剂。令人惊讶的是，我们还发现该化合物可以抑制另外 5 个 hTAS2R，包括密切相关的受体 hTAS2R43。分子建模和定点诱变研究表明，七号螺旋中的两个残基对于 hTAS2R43/31 的拮抗剂活性很重要。在人体感官试验中，GIV3727 显着降低了两种磺酰胺甜味剂的苦味，表明 TAS2R 拮抗剂在体内具有活性。我们的结果表明，小分子苦味受体拮抗剂可以有效降低食品、饮料和药品的苦味品质。
Human bitter taste is mediated by the hTAS2R family of G protein-coupled receptors. The discovery of the hTAS2Rs enables the potential to develop specific bitter receptor antagonists that could be beneficial as chemical probes to examine the role of bitter receptor function in gustatory and non-gustatory tissues. In addition, they could have widespread utility in food and beverages fortified with vitamins, antioxidants and other nutraceuticals since many of these have unwanted bitter aftertastes. We employed a high-throughput screening approach to discover a novel bitter receptor antagonist (GIV3727) that inhibits activation of hTAS2R31 by saccharin and acesulfame K, two common artificial sweeteners. Pharmacological analyses revealed that GIV3727 likely acts as an orthosteric, insurmountable antagonist of hTAS2R31. Surprisingly, we also found that this compound could inhibit five additional hTAS2Rs, including the closely related receptor hTAS2R43. Molecular modeling and site-directed mutagenesis studies suggest that two residues in helix seven are important for antagonist activity in hTAS2R43/31. In human sensory trials, GIV3727 significantly reduced the bitterness associated with the two sulphonamide sweeteners, indicating that TAS2R antagonists are active in vivo. Our results demonstrate that small molecule bitter receptor antagonists can effectively reduce the bitter taste qualities of foods, beverages, and pharmaceuticals.
登录
查看更多内容
影响因子：
30.8
作者：
Bufe, B;Hofmann, T;Meyerhof, W
通讯作者：
Meyerhof, W
影响因子：
64.8
作者：
Matsunami, H;Montmayeur, JP;Buck, LB
通讯作者：
Buck, LB
影响因子：
64.5
作者：
Adler, E;Hoon, MA;Zuker, CS
通讯作者：
Zuker, CS
影响因子：
64.8
作者：
Rosenbaum, Daniel M.;Rasmussen, Soren G. F.;Kobilka, Brian K.
通讯作者：
Kobilka, Brian K.
影响因子：
9.2
作者：
Bufe, B;Breslin, PAS;Meyerhof, W
通讯作者：
Meyerhof, W