Herbal Modulators of the Human Sweet-Taste Receptor (TAS1R2 / TAS1R3)

Abstract

The human sweet-taste receptor (STR), a heterodimer of the class-C GPCR subunits TAS1R2 (Taste Receptor Type 1 Member 2) and TAS1R3 (Taste Receptor Type 1 Member 3), is the pivotal molecular sensor of dietary sugars and an emerging metabolic regulator in extra-oral tissues. A striking proportion of STR ligands originate from plants, encompassing diterpene glycosides (steviol glycosides), cucurbitane triterpenoids (mogrosides), triterpenoid saponins (gymnemic acids), flavanone derivatives (neohesperidin dihydrochalcone, eriodictyol), and intensely sweet proteins (thaumatin, brazzein, miraculin, curculin). These “herbal” molecules do far more than replace sucrose: they can act as full agonists, positive allosteric modulators, biased agonists, or competitive antagonists, thereby reshaping STR-mediated pathways that control incretin release, insulin secretion, and appetite.

This review maps the chemistry, binding topography, and signalling bias of major botanical STR modulators; evaluates pre-clinical and clinical evidence for their metabolic effects; and discusses formulation tactics that exploit sweet-enhancing synergy or mitigate off-tastes. Safety and regulatory statuses are summarised, highlighting generally recognised as safe (GRAS) approvals for steviol glycosides, monk-fruit extracts, and recombinant sweet proteins, alongside the hypertensive risk of glycyrrhizin and the sweet-suppression utility of gymnemic acids. Analytical toolkits—including LC-MS/MS quantification, cell-based calcium assays, and human psychophysics—are outlined for rigorous characterisation.

Finally, the review identifies key knowledge gaps: the need for high-resolution STR–herbal co-structures, development of gut-restricted allosteric modulators, clarification of microbiome interactions, and precision-nutrition strategies that accommodate TAS1R polymorphisms. Collectively, botanical STR modulators represent a versatile pharmaco-nutritional arsenal with the potential to curb caloric sugar intake and ameliorate metabolic disease, provided that forthcoming research translates their promise into clinically validated interventions.