Flavor is perceived through the olfactory, taste, and trigeminal systems, mediated by designated GPCRs and channels. Signal integration occurs mainly in the brain, but some cross-reactivities occur at the receptor level. Here, we predict potential bitterness and taste receptors targets for thousands of odorants. BitterPredict and BitterIntense classifiers suggest that 3–9% of flavor and food odorants have bitter taste, but almost none are intensely bitter. About 14% of bitter molecules are expected to have an odor. Bitterness is more common for unpleasant smells such as fishy, amine, and ammoniacal, while non-bitter odorants often have pleasant smells. Experimental toxicity values suggest that fishy ammoniac smells are more toxic than pleasant smells, regardless of bitterness. TAS2R14 is predicted as the main bitter receptor for odorants, confirmed by in vitro profiling of 10 odorants. The activity of bitter odorants may have implications for physiology due to ectopic expression of taste and smell receptors.Flavor is perceived through the olfactory, taste, and trigeminal systems, mediated by designated GPCRs and channels. Signal integration occurs mainly in the brain, but some cross-reactivities occur at the receptor level. Here, we predict potential bitterness and taste receptors targets for thousands of odorants. BitterPredict and BitterIntense classifiers suggest that 3–9% of flavor and food odorants have bitter taste, but almost none are intensely bitter. About 14% of bitter molecules are expected to have an odor. Bitterness is more common for unpleasant smells such as fishy, amine, and ammoniacal, while non-bitter odorants often have pleasant smells. Experimental toxicity values suggest that fishy ammoniac smells are more toxic than pleasant smells, regardless of bitterness. TAS2R14 is predicted as the main bitter receptor for odorants, confirmed by in vitro profiling of 10 odorants. The activity of bitter odorants may have implications for physiology due to ectopic expression of taste and smell receptors.

The human GPCR family comprises circa 800 members, activated by hundreds of thousands of compounds. Bitter taste receptors, TAS2Rs, constitute a large and distinct subfamily, expressed orally and extra-orally and involved in physiological and pathological conditions. TAS2R14 is the most promiscuous member, with over 150 agonists and 3 antagonists known prior to this study. Due to the scarcity of inhibitors and to the importance of chemical probes for exploring TAS2R14 functions, we aimed to discover new ligands for this receptor, with emphasis on antagonists. To cope with the lack of experimental structure of the receptor, we used a mixed experimental/computational methodology which iteratively improved the performance of the predicted structure. The increasing number of active compounds, obtained here through experimental screening of FDA-approved drug library, and through chemically synthesized flufenamic acid derivatives, enabled the refinement of the binding pocket, which in turn improved the structure-based virtual screening reliability. This mixed approach led to the identification of 10 new antagonists and 200 new agonists of TAS2R14, illustrating the untapped potential of rigorous medicinal chemistry for TAS2Rs. 9% of the ~ 1800 pharmaceutical drugs here tested activate TAS2R14, nine of them at sub-micromolar concentrations. The iterative framework suggested residues involved in the activation process, is suitable for expanding bitter and bitter-masking chemical space, and is applicable to other promiscuous GPCRs lacking experimental structures.

We have previously shown that L-glucose, the non-caloric enantiomer of D-glucose, activates the human sweet taste receptor T1R2/T1R3 transiently expressed in HEK293T cells. Here we show that D- and L-glucose can also activate T1R2 and T1R3 expressed without the counterpart monomer. Serine mutation to alanine in residue 147 in the binding site of T1R3 VFT domain, completely abolishes T1R3S147A activation by either L or D-glucose, while T1R2/T1R3S147A responds in the same way as T1R2 expressed without its counterpart. We further show that the original T1R2 reference sequence (NM\_152232.1) is less sensitive by almost an order of magnitude than reference sequence at the time this study was performed (NM\_152232.4). We find that out of the four differing positions, it is the R317G in the VFT domain of T1R2, that is responsible for this effect in-vitro. It is important both for practical assay sensitivity, and because glycine is found in this position in  20\% of the world population. While the effects of the mutations and of the partial transfections were similar for D and L enantiomers, their dose response curves remained distinct, with L-glucose reaching an early plateau.

Taste dysfunctions may occur, for example, after viral infection, surgery, medications, or with age. In clinical practice, it is important to assess patients’ taste function with rapidity and reliability. This study aimed to develop a test that assesses human gustatory sensitivity together with somatosensory functions of astringency and spiciness. A total of 154 healthy subjects and 51 patients with chemosensory dysfunction rated their gustatory sensitivity. They underwent a whole-mouth identification test of 12 filter-paper strips impregnated with low and high concentrations of sweet, sour, salty, bitter (sucrose, citric acid, NaCl, quinine), astringency (tannin), and spiciness (capsaicin). The percentage of correct identifications for high-concentrated sweet and sour, and for low-concentrated salty, bitter and spicy was lower in patients as compared with healthy participants. Interestingly, a lower identification in patients for both astringent concentrations was found. Based on the results, we proposed the Seven-iTT to assess chemo/somatosensory function, with a cut-off of 6 out of 7. The test score discriminated patients from healthy controls and showed gender differences among healthy controls. This quantitative test seems to be suitable for routine clinical assessment of gustatory and trigeminal function. It also provides new evidence on the mutual interaction between the two sensory systems.

Taste GPCRs are expressed in taste buds on the tongue and play a key role in food choice and consumption. They are also expressed extra-orally, with various physiological roles that are currently under study. Unraveling the roles of these receptors relies on the knowledge of their ligands. Combining sensory, cell-based and computational approaches enabled the discovery of numerous agonists and several antagonists. Here we provide a short overview of taste receptor families, main recent methods for ligands discovery, and current sources of information about known ligands. The future directions that are likely to impact the taste GPCR field include focus on ligand interactions with naturally occurring polymorphisms, as well as harnessing the power of CryoEM and of multiple signaling readout techniques.

Sweet taste is innately appealing, ensuring that mammals are attracted to the sweetness of mother’s milk and other sources of carbohydrates and calories. In the modern world, the availability of sugars and sweeteners and the eagerness of the food industry to maximize palatability, result in an abundance of sweet food products, which poses a major health challenge. The aim of the current study is to analyze sweetness levels, liking, and ingredients of online reviews of food products, in order to obtain insights into sensory nutrition and to identify new opportunities for reconciling the palatability–healthiness tension. We collected over 200,000 reviews of  30,000 products on Amazon dated from 2002 to 2012 and  350,000 reviews of  2400 products on iHerb from 2006 to 2021. The reviews were classified and analyzed using manual curation, natural language processing, and machine learning. In total,  32,000 (Amazon) and  29,000 (iHerb) of these reviews mention sweetness, with 2200 and 4600 reviews referring to the purchased products as oversweet. Oversweet reviews were dispersed among consumers. Products that included sucralose had more oversweet reviews than average. 26 products had at least 50 reviews for which at least 10% were oversweet. For these products, the average liking by consumers reporting oversweetness was significantly lower (by 0.9 stars on average on a 1 to 5 stars scale) than by the rest of the consumers. In summary, oversweetness appears in 7–16% of the sweetness-related reviews and is less liked, which suggests an opportunity for customized products with reduced sweetness. These products will be simultaneously healthier and tastier for a substantial subgroup of customers and will benefit the manufacturer by expanding the products’ target audience. Analysis of consumers’ reviews of marketed food products offers new ways to obtain informative sensory data.

Abstract Subjectively perceived impairment of taste is a common and distinct symptom of coronavirus disease 2019 (COVID-19). Large meta-analyses identified this symptom in approximately 50% of cases. However, this high prevalence is not supported by blinded and validated psychophysical gustatory testing, which showed a much lower prevalence in up to 26% of patients. This discrepancy may be due to misinterpretation of impaired retronasal olfaction as gustatory dysfunction. In addition, we hypothesized that COVID-19?associated hyposmia is involved in the decrease of gustatory function, as found for hyposmia of different origin. This indirect mechanism would be based on the central-nervous mutual amplification between the chemical senses, which fails in COVID-19?associated olfactory loss. However, further research is necessary on how severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) may directly impair the gustatory pathway as well as its subjective perception.

Neoantigens are now recognized drivers of the antitumor immune response. Recurrent neoantigens, shared among groups of patients, have thus become increasingly coveted therapeutic targets. Here, we report on the data-driven identification of a robustly presented, immunogenic neoantigen that is derived from the combination of HLA-A*01:01 and RAS.Q61K. Analysis of large patient cohorts indicated that this combination applies to 3% of patients with melanoma. Using HLA peptidomics, we were able to demonstrate robust endogenous presentation of the neoantigen in 10 tumor samples. We detected specific reactivity to the mutated peptide within tumor-infiltrating lymphocytes (TILs) from 2 unrelated patients, thus confirming its natural immunogenicity. We further investigated the neoantigen-specific clones and their T cell receptors (TCRs) via a combination of TCR sequencing, TCR overexpression, functional assays, and single-cell transcriptomics. Our analysis revealed a diverse repertoire of neoantigen-specific clones with both intra-and interpatient TCR similarities. Moreover, 1 dominant clone proved to cross-react with the highly prevalent RAS.Q61R variant. Transcriptome analysis revealed a high association of TCR clones with specific T cell phenotypes in response to cognate melanoma, with neoantigen-specific cells showing an activated and dysfunctional phenotype. Identification of recurrent neoantigens and their reactive TCRs can promote ``off-the shelf'' precision immunotherapies, alleviating limitations of personalized treatments.

Obesity is a global epidemic that causes morbidity and impaired quality of life. The melanocortin receptor 4 (MC4R) is at the crux of appetite, energy homeostasis, and body-weight control in the central nervous system and is a prime target for anti-obesity drugs. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human MC4R-Gs signaling complex bound to the agonist setmelanotide, a cyclic peptide recently approved for the treatment of obesity. The work reveals the mechanism of MC4R activation, highlighting a molecular switch that initiates satiation signaling. In addition, our findings indicate that calcium (Ca2+) is required for agonist, but not antagonist, efficacy. These results fill a gap in the understanding of MC4R activation and could guide the design of future weight-management drugs.

Background. Clinical diagnosis of coronavirus disease 2019 (COVID-19) is essential to the detection and prevention of COVID-19. Sudden onset of loss of taste and smell is a hallmark of COVID-19, and optimal ways for including these symptoms in the screening of patients and distinguishing COVID-19 from other acute viral diseases should be established. Methods. We performed a case-control study of patients who were polymerase chain reaction-tested for COVID-19 (112 positive and 112 negative participants), recruited during the first wave (March 2020-May 2020) of the COVID-19 pandemic in Israel. Patients reported their symptoms and medical history by phone and rated their olfactory and gustatory abilities before and during their illness on a 1-10 scale. Results. Changes in smell and taste occurred in 68% (95% CI, 60%-76%) and 72% (95% CI, 64%-80%) of positive patients, with odds ratios of 24 (range, 11-53) and 12 (range, 6-23), respectively. The ability to smell was decreased by 0.5 +/- 1.5 in negatives and by 4.5 +/- 3.6 in positives. A penalized logistic regression classifier based on 5 symptoms had 66% sensitivity, 97% specificity, and an area under the receiver operating characteristics curve (AUC) of 0.83 on a holdout set. A classifier based on degree of smell change was almost as good, with 66% sensitivity, 97% specificity, and 0.81 AUC. The predictive positive value of this classifier was 0.68, and the negative predictive value was 0.97. Conclusions. Self-reported quantitative olfactory changes, either alone or combined with other symptoms, provide a specific tool for clinical diagnosis of COVID-19. A simple calculator for prioritizing COVID-19 laboratory testing is presented here. [GRAPHICS] .

Naturally occurring sugars usually have d-chirality. While a change in chirality typically affects ligand–receptor interaction, non-caloric l-glucose was reported as sweet for humans. Here we show that l- and d-glucose have similar sensory detection thresholds (0.041 ± 0.006 M for d-glucose, and 0.032 ± 0.007 M for l-glucose) and similar sweetness intensities at suprathreshold concentrations. We demonstrate that l-glucose acts via the sweet taste receptor TAS1R2/TAS1R3, eliciting a dose-dependent activation in cell-based functional assays. Computational docking of glucose to the VFT domain of TAS1R2 suggests two sub-pockets, each compatible with each of the enantiomers. While some polar residues (Y103, D142, N143, S144, Y215) are unique for sub-pocket A and others (D307, T326, E382, R383) for sub-pocket B, no interaction is unique for only one enantiomer. The many options for creating hydrogen bonds with the hydroxyl moieties of glucose explain how both enantiomers can fit each one of the sub-pockets.

Drug development is a long, expensive and multistage process geared to achieving safe drugs with high efficacy. A crucial prerequisite for completing the medication regimen for oral drugs, particularly for pediatric and geriatric populations, is achieving taste that does not hinder compliance. Currently, the aversive taste of drugs is tested in late stages of clinical trials. This can result in the need to reformulate, potentially resulting in the use of more animals for additional toxicity trials, increased financial costs and a delay in release to the market. Here we present BitterIntense, a machine learning tool that classifies molecules into “very bitter” or “not very bitter”, based on their chemical structure. The model, trained on chemically diverse compounds, has above 80% accuracy on several test sets. Our results suggest that about 25% of drugs are predicted to be very bitter, with even higher prevalence (~40%) in COVID19 drug candidates and in microbial natural products. Only ~10% of toxic molecules are predicted to be intensely bitter, and it is also suggested that intense bitterness does not correlate with hepatotoxicity of drugs. However, very bitter compounds may be more cardiotoxic than not very bitter compounds, possessing significantly lower QPlogHERG values. BitterIntense allows quick and easy prediction of strong bitterness of compounds of interest for food, pharma and biotechnology industries. We estimate that implementation of BitterIntense or similar tools early in drug discovery process may lead to reduction in delays, in animal use and in overall financial burden.

Smell loss is important for coronavirus disease-2019 (COVID-19) screening and diagnosis. Particular attention should be paid to individuals with pre-COVID-19 chronic hyposmia or anosmia. We report a case of reversible taste impairment in a COVID-19 patient with chronically impaired sense of smell. This case emphasizes the importance of COVID-19-related taste assessment.

ObjectivesTo characterize longitudinal symptoms of mild coronavirus disease 2019 (COVID-19) patients for a period of 6 months, to potentially aid in disease management. Methods Phone interviews were conducted with 103 patients with mild COVID-19 in Israel over a 6-month period (April 2020 to October 2020). Patients were recruited via social media and word to mouth and were interviewed up to 4 times, depending on reports of their unresolved symptoms. Inclusion criteria required participants to be residents of Israel aged 18 years or older, with positive COVID-19 real-time PCR results and nonsevere symptoms. The onset, duration, severity and resolution of symptoms were analysed. Results A total of 44% (45/103), 41% (42/103), 39% (40/103) and 38% (39/103) of patients experienced headache, fever, muscle ache and dry cough as the first symptom respectively. Smell and taste changes were experienced at 3.9 ± 5.4 and 4.6 ± 5.7 days (mean ± standard deviation (SD)) after disease onset respectively. Among prevalent symptoms, fever had the shortest duration (5.8 ± 8.6 days), and taste and smell changes were the longest-lasting symptoms (17.2 ± 17.6 and 18.9 ± 19.7 days; durations censored at 60 days). Longer recovery of the sense of smell correlated with the extent of smell change. At the 6-month follow-up, 46% (47/103) of the patients had at least one unresolved symptom, most commonly fatigue (22%, 23/103), smell and taste changes (15%, 15/103 and 8%, 8/103 respectively) and breathing difficulties (8%, 8/103). Conclusions Long-lasting effects of mild COVID-19 manifested in almost half of the participants reporting at least one unresolved symptom after 6 months.

Obesity is a global epidemic causing morbidity and impaired quality of life. The melanocortin receptor 4 (MC4R) is at the crux of appetite, energy homeostasis, and body-weight control in the central nervous system and is a prime target for anti-obesity drugs. Here, we present the cryo-EM structure of the human MC4R-Gs signaling complex bound to the agonist setmelanotide, a cyclic peptide recently approved for the treatment of obesity. The work reveals the mechanism of MC4R activation, highlighting a molecular switch that initiates satiation signaling. In addition, our findings indicate that Ca2+ is required for agonist but not antagonist efficacy. These results fill a gap in understanding MC4R activation and could guide the design of future weight management drugs.

Hydrogen to deuterium isotopic substitution has only a minor effect on physical and chemical properties of water and, as such, is not supposed to influence its neutral taste. Here we conclusively demonstrate that humans are, nevertheless, able to distinguish D2O from H2O by taste. Indeed, highly purified heavy water has a distinctly sweeter taste than same-purity normal water and can add to perceived sweetness of sweeteners. In contrast, mice do not prefer D2O over H2O, indicating that they are not likely to perceive heavy water as sweet. HEK 293T cells transfected with the TAS1R2/TAS1R3 heterodimer and chimeric G-proteins are activated by D2O but not by H2O. Lactisole, which is a known sweetness inhibitor acting via the TAS1R3 monomer of the TAS1R2/TAS1R3, suppresses the sweetness of D2O in human sensory tests, as well as the calcium release elicited by D2O in sweet taste receptor-expressing cells. The present multifaceted experimental study, complemented by homology modelling and molecular dynamics simulations, resolves a long-standing controversy about the taste of heavy water, shows that its sweet taste is mediated by the human TAS1R2/TAS1R3 taste receptor, and opens way to future studies of the detailed mechanism of action.

Recent anecdotal and scientific reports have provided evidence of a link between COVID-19 and chemosensory impairments, such as anosmia. However, these reports have downplayed or failed to distinguish potential effects on taste, ignored chemesthesis, and generally lacked quantitative measurements. Here, we report the development, implementation, and initial results of a multilingual, international questionnaire to assess self-reported quantity and quality of perception in 3 distinct chemosensory modalities (smell, taste, and chemesthesis) before and during COVID-19. In the first 11 days after questionnaire launch, 4039 participants (2913 women, 1118 men, and 8 others, aged 19-79) reported a COVID-19 diagnosis either via laboratory tests or clinical assessment. Importantly, smell, taste, and chemesthetic function were each significantly reduced compared to their status before the disease. Difference scores (maximum possible change +/- 100) revealed a mean reduction of smell (-79.7 +/- 28.7, mean +/- standard deviation), taste (-69.0 +/- 32.6), and chemesthetic (-37.3 +/- 36.2) function during COVID-19. Qualitative changes in olfactory ability (parosmia and phantosmia) were relatively rare and correlated with smell loss. Importantly, perceived nasal obstruction did not account for smell loss. Furthermore, chemosensory impairments were similar between participants in the laboratory test and clinical assessment groups. These results show that COVID-19-associated chemosensory impairment is not limited to smell but also affects taste and chemesthesis.The multimodal impact of COVID-19 and the lack of perceived nasal obstruction suggest that severe acute respiratory syndrome coronavirus strain 2 (SARS-CoV-2) infection may disrupt sensory-neural mechanisms.