Topical application of a P2X2/P2X3 purine receptor inhibitor suppresses the bitter taste of medicines and other taste qualities.

BACKGROUND AND PURPOSE: Many medications taste intensely bitter. The innate aversion to bitterness affects medical compliance, especially in children. There is a clear need to develop bitter blockers to suppress the bitterness of vital medications. Bitter taste is mediated by TAS2R receptors. Because different pharmaceutical compounds activate distinct sets of TAS2Rs, targeting specific receptors may only suppress bitterness for certain, but not all, bitter-tasting compounds. Alternative strategies are needed to identify universal bitter blockers that will improve the acceptance of every medication. Taste cells in the mouth transmit signals to afferent gustatory nerve fibres through the release of ATP, which activates the gustatory nerve-expressed purine receptors P2X2/P2X3. We hypothesized that blocking gustatory nerve transmission with P2X2/P2X3 inhibitors (e.g. 5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidine-2,4-diamine [AF-353]) would reduce bitterness for all medications and bitter compounds. EXPERIMENTAL APPROACH: Human sensory taste testing and mouse behavioural analyses were performed to determine if oral application of AF-353 blocks perception of bitter taste and other taste qualities but not non-gustatory oral sensations (e.g. tingle). KEY RESULTS: Rinsing the mouth with AF-353 in humans or oral swabbing it in mice suppressed the bitter taste and avoidance behaviours of all compounds tested. We further showed that AF-353 suppressed other taste qualities (i.e. salt, sweet, sour and savoury) but had no effects on other oral or nasal sensations (e.g, astringency and oral tingle). CONCLUSION AND IMPLICATIONS: This is the first time a universal, reversible taste blocker in humans has been reported. Topical application of P2X2/P2X3 inhibitor to suppress bitterness may improve medical compliance.

Paxlovid mouth likely is mediated by activation of the TAS2R1 bitter receptor by nirmatrelvir.

Coronavirus disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has remained a public health threat since late 2019. Among the strategies rapidly developed to prevent and treat COVID-19, the antiviral medication Paxlovid (nirmatrelvir/ritonavir combination) has shown remarkable efficacy in reducing viral load and relieving clinical symptoms. Unexpectedly, a persistent bitter/bad taste, referred to as "Paxlovid mouth", has been frequently noted. Consistent with this, dysgeusia (altered taste) is listed as a main adverse effect of Paxlovid based on clinical trial data. Nirmatrelvir inhibits Mpro, a SARS-CoV-2 main protease, whereas ritonavir prolongs the activity of nirmatrelvir by slowing its metabolism. Prior usage of ritonavir in other conditions has not been linked to a persistent bad taste, despite the fact that ritonavir tastes bitter. Therefore, we hypothesized that nirmatrelvir may account for Paxlovid mouth by activating one or more of the 25 human TAS2R bitter taste receptors. Here, we show that TAS2R1 is the primary bitter receptor activated by nirmatrelvir, at concentrations as low as 15 µM, which overlaps with plasma concentrations of nirmatrelvir in a subset of patients. We also show that saccharin, a non-nutritive sweetener that may block the activity of TAS2R1, has little or no effect on nirmatrelvir-stimulated TAS2R1 activity. Such findings may help identify novel strategies to alleviate Paxlovid mouth and increase treatment compliance.