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Objective Psammomys obesus gerbil exhibits PKC over-expression on high-energy (HE) diet. Muscle insulin receptor (IR) signalling and tyrosine kinase activity are inhibited eliciting insulin resistance. We aimed at preventing diabetes by inhibiting PKC-induced serine phosphorylation of IRS-1 with novel PKC abrogating peptides. Research design PKC abrogating peptides were copied from catalytic domain of PKC molecule (PCT patent IL2006/000755). Psammomys fed a diabetogenic HE diet received i.p. peptides KCe-12 and KCe-16 (18 mg/kg) on days 0, 7 and 14 controls received peptide solvent. Results Food consumption and animal weight remained unchanged. On day 16, non-fasting blood glucose levels returned to normal (90 ± 5 versus 347 ± 16 mg/dL in untreated controls). Hyperinsulinemia fell from 584 ± 55 to 180 ± 22 mU/L. Western blot analysis showed that the increased phosphoserine636, 639 content on IRS-1 in gastrocnemius muscle of diabetic animals was reduced three fold, the PKB/AKT activity increased two fold and muscle GLUT4 tended to increase, compared with controls. Likewise, administration of KCe-12 prior to placing the HE diet prevented the onset of diabetes. KCe-12 treatment did not reduce muscle PKC level. Damage and loss of insulin in pancreatic beta cells on HE diet were prevented by KCe-12, as shown in micrographs of islet hematoxylin-eosin staining and insulin immunostaining. The preserved secretory function enabled Psammomys to normalize glucose homeostasis. Conclusions KCe-16 and KCe-12 peptides derived from PKC substrate-binding region prevented the nutritional diabetes and protected muscle IRS-1 from PKC-induced serine phosphorylation, abrogating the insulin-signalling impediment in the Psammomys model of type 2 diabetes. Anti-diabetic peptides may lead to novel modalities preventing human overnutrition-induced insulin resistance and diabetes. [ABSTRACT FROM AUTHOR]

Bitter compounds are common in nature and among drugs. Previously, machine learning tools were developed to predict bitterness from the chemical structure. However, known structures are estimated to represent only 5-10% of the metabolome, and the rest remain unassigned or "dark". We present BitterMasS, a Random Forest classifier that was trained on 5414 experimental mass spectra of bitter and nonbitter compounds, achieving precision = 0.83 and recall = 0.90 for an internal test set. Next, the model was tested against spectra newly extracted from the literature 106 bitter and nonbitter compounds and for additional spectra measured for 26 compounds. For these external test cases, BitterMasS exhibited 67% precision and 93% recall for the first and 58% accuracy and 99% recall for the second. The spectrum-bitterness prediction strategy was more effective than the spectrum-structure-bitterness prediction strategy and covered more compounds. These encouraging results suggest that BitterMasS can be used to predict bitter compounds in the metabolome without the need for structural assignment of individual molecules. This may enable identification of bitter compounds from metabolomics analyses, for comparing potential bitterness levels obtained by different treatments of samples and for monitoring bitterness changes overtime.

Purpose: gustatory ability is a marker of health not routinely tested in the medical practice. The current study wants to assess whether taste strips can be useful to monitor taste function from home., Methods: we performed simple sensory tests in lab setting vs. unassisted testing at home, and compared the results with self-reports ability to taste and smell. Using paper strips impregnated with sweet, bitter, salty, or sour tastants, and with two trigeminal stimuli (capsaicin, tannins) in high and low concentrations, we assessed gustatory and trigeminal function in 74 participants (47 women) in the lab, where paper strips were administered by an experimenter, and in 77 participants (59 women) at home, where they self-administered the test., Results: we found that high (but not low) concentration taste strips are correctly identified by vast majority of participants. On average, taste identification, intensity and pleasantness scores did not differ for the 8 taste strips, while identification of capsaicin was significantly better in the lab. Taste identification scores correlated with intensity ratings in both settings (r = 0.56, in the lab, r = 0.48, at home, p < 0.005). Self-rated taste ability correlated with self-rated smell ability (r = 0.68, and r = 0.39, p ≤ 0.005), but not with scores in the strips test., Conclusion: home testing with impregnated taste strips is feasible, and can be used for telemedical purposes., (© 2024. The Author(s).)

A large portion of the human GPCRome is still in the dark and understudied, consisting even of entire subfamilies of GPCRs such as odorant receptors, class A and C orphans, adhesion GPCRs, Frizzleds and taste receptors. However, it is undeniable that these GPCRs bring an untapped therapeutic potential that should be explored further. Open questions on these GPCRs span diverse topics such as deorphanisation, the development of tool compounds and tools for studying these GPCRs, as well as understanding basic signalling mechanisms. This review gives an overview of the current state of knowledge for each of the diverse subfamilies of understudied receptors regarding their physiological relevance, molecular mechanisms, endogenous ligands and pharmacological tools. Furthermore, it identifies some of the largest knowledge gaps that should be addressed in the foreseeable future and lists some general strategies that might be helpful in this process., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Bitter taste receptors (T2R) are a subfamily of G protein-coupled receptors that enable humans to detect aversive and toxic substances. The ability to discern bitter compounds varies between individuals and is attributed mainly to naturally occurring T2R polymorphisms. T2Rs are also expressed in numerous non-gustatory tissues, including the heart, indicating potential contributions to cardiovascular physiology. In this study. T2Rs that have previously been identified in human cardiac tissues (T2Rs - 10, 14, 30, 31, 46 and 50) and their naturally occurring polymorphisms were functionally characterised. The ligand-dependent signaling responses of some T2R variants were completely abolished (T2R30 Leu 252 and T2R46 Met 228 ), whereas other receptor variants had moderate changes in their maximal response, but not potency, relative to wild type. Using a cAMP fluorescent biosensor, we reveal the productive coupling of T2R14, but not the T2R14 Phe 201 variant, to endogenous Gα i . Modeling revealed that these variants resulted in altered interactions that generally affected ligand binding (T2R30 Leu 252 ) or Gα protein interactions (T2R46 Met 228 and T2R14 Phe 201 ), rather than receptor structural stability. Interestingly, this study is the first to show a difference in signaling for T2R50 Tyr 203 (rs1376251) which has been associated with cardiovascular disease. The observation of naturally occurring functional variation in the T2Rs with the greatest expression in the heart is important, as their discovery should prove useful in deciphering the role of T2Rs within the cardiovascular system., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There is a prevailing view that humans' capacity to use language to characterize sensations like odors or tastes is poor, providing an unreliable source of information., Methods: Here, we developed a machine learning method based on Natural Language Processing (NLP) using Large Language Models (LLM) to predict COVID-19 diagnosis solely based on text descriptions of acute changes in chemosensation, i.e., smell, taste and chemesthesis, caused by the disease. The dataset of more than 1500 subjects was obtained from survey responses early in the COVID-19 pandemic, in Spring 2020., Results: When predicting COVID-19 diagnosis, our NLP model performs comparably (AUC ROC ~ 0.65) to models based on self-reported changes in function collected via quantitative rating scales. Further, our NLP model could attribute importance of words when performing the prediction; sentiment and descriptive words such as "smell", "taste", "sense", had strong contributions to the predictions. In addition, adjectives describing specific tastes or smells such as "salty", "sweet", "spicy", and "sour" also contributed considerably to predictions., Conclusions: Our results show that the description of perceptual symptoms caused by a viral infection can be used to fine-tune an LLM model to correctly predict and interpret the diagnostic status of a subject. In the future, similar models may have utility for patient verbatims from online health portals or electronic health records., (© 2023. The Author(s).)

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., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The bitter taste receptor TAS2R14 is a G protein-coupled receptor that is found on the tongue as well as in the human airway smooth muscle and other extraoral tissues. Because its activation causes bronchodilatation, TAS2R14 is a potential target for the treatment of asthma or chronic obstructive pulmonary disease. Structural variations of flufenamic acid, a nonsteroidal anti-inflammatory drug, led us to 2-aminopyridines showing considerable efficacy and potency in an IP 1 accumulation assay. In combination with an exchange of the carboxylic moiety by a tetrazole unit, a set of promising new TAS2R14 agonists was developed. The most potent ligand 28.1 (EC 50 = 72 nM) revealed a six-fold higher potency than flufenamic acid and a maximum efficacy of 129%. Besides its unprecedented TAS2R14 activation, 28.1 revealed marked selectivity over a panel of 24 non-bitter taste human G protein-coupled receptors.

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&#95;152232.1) is less sensitive by almost an order of magnitude than the reference sequence at the time this study was performed (NM&#95;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 significant for both practical assay sensitivity and because glycine is found in this position in ~20% of the world population. While the effects of the mutations and the partial transfections were similar for d and l enantiomers, their dose-response curves remained distinct, with l-glucose reaching an early plateau., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Bitter taste receptors (T2Rs) are G protein‑coupled receptors originally detected in the gustatory system. More recently, T2Rs have been shown to be expressed in extra‑oral cells eliciting non‑gustatory functions. Emerging evidence has suggested a potential role for T2R signaling in diverse pathophysiological conditions, including cancer. -The aim of the present study was to evaluate the expression of T2R14 in pancreatic ductal adenocarcinoma (PDAC) and to assess its involvement in the anticancer effects induced by apigenin, a natural ligand of T2R14. For this purpose, T2R14 expression was explored in PDAC tumor tissue and tumor‑derived cell lines. Using the cell lines expressing the highest levels of T2R14, its effects on chemoresponsiveness and migration upon activation with apigenin were investigated in vitro . To the best of our knowledge, the present study was the first to confirm the expression of the T2R family member T2R14 in PDAC. Patients with relatively high levels of T2R14 expression exhibited significantly prolonged overall survival compared with that of patients with low T2R14 expression. Furthermore, novel functions for apigenin were revealed; notably, apigenin was shown to elicit cytotoxic, anti‑migratory and chemosensitizing effects to 5‑fluoruracil (5‑FU) and to 5‑FU, leucovorin, irinotecan and oxaliplatin in pancreatic cancer cells. In conclusion, the present study extended the evidence for the anticancer effects of apigenin and strongly indicated the functional relevance of T2R14 in PDAC, even though their respective underlying pathways appear to be independent of each other.

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.

Bitterness is an aversive cue elicited by thousands of chemically diverse compounds. Bitter taste may prevent consumption of foods and jeopardize drug compliance. The G protein-coupled receptors for bitter taste, TAS2Rs, have species-dependent number of subtypes and varying expression levels in extraoral tissues. Molecular recognition by TAS2R subtypes is physiologically important, and presents a challenging case study for ligand-receptor matchmaking. Inspired by hybrid recommendation systems, we developed a new set of similarity features, and created the BitterMatch algorithm that predicts associations of ligands to receptors with ~ 80% precision at ~ 50% recall. Associations for several compounds were tested in-vitro, resulting in 80% precision and 42% recall. The encouraging performance was achieved by including receptor properties and integrating experimentally determined ligand-receptor associations with chemical ligand-to-ligand similarities.BitterMatch can predict off-targets for bitter drugs, identify novel ligands and guide flavor design. The novel features capture information regarding the molecules and their receptors, which could inform various chemoinformatic tasks. Inclusion of neighbor-informed similarities improves as experimental data mounts, and provides a generalizable framework for molecule-biotarget matching., (© 2022. The Author(s).)

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.

Background: Sudden smell loss is a specific early symptom of COVID-19, which, prior to the emergence of Omicron, had estimated prevalence of ~40% to 75%. Chemosensory impairments affect physical and mental health, and dietary behavior. Thus, it is critical to understand the rate and time course of smell recovery. The aim of this cohort study was to characterize smell function and recovery up to 11 months post COVID-19 infection., Methods: This longitudinal survey of individuals suffering COVID-19-related smell loss assessed disease symptoms and gustatory and olfactory function. Participants (n=12,313) who completed an initial survey (S1) about respiratory symptoms, chemosensory function and COVID-19 diagnosis between April and September 2020, were invited to complete a follow-up survey (S2). Between September 2020 and February 2021, 27.5% participants responded (n=3,386), with 1,468 being diagnosed with COVID-19 and suffering co-occurring smell and taste loss at the beginning of their illness., Results: At follow-up (median time since COVID-19 onset ~200 days), ~60% of women and ~48% of men reported less than 80% of their pre-illness smell ability. Taste typically recovered faster than smell, and taste loss rarely persisted if smell recovered. Prevalence of parosmia and phantosmia was ~10% of participants in S1 and increased substantially in S2: ~47% for parosmia and ~25% for phantosmia. Persistent smell impairment was associated with more symptoms overall, suggesting it may be a key marker of long-COVID illness. The ability to smell during COVID-19 was rated slightly lower by those who did not eventually recover their pre-illness ability to smell at S2., Conclusions: While smell ability improves for many individuals who lost it during acute COVID-19, the prevalence of parosmia and phantosmia increases substantially over time. Olfactory dysfunction is associated with broader persistent symptoms of COVID-19, and may last for many months following acute COVID-19. Taste loss in the absence of smell loss is rare. Persistent qualitative smell symptoms are emerging as common long-term sequelae; more research into treatment options is strongly warranted given that even conservative estimates suggest millions of individuals may experience parosmia following COVID-19. Healthcare providers worldwide need to be prepared to treat post COVID-19 secondary effects on physical and mental health.

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., (© 2021 The Authors. International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Licorice saponins, the main constituents of Glycyrrhiza glabra L. roots, are highly appreciated by the consumer for their pleasant sweet and long lasting licorice taste. The objective of the present study was to understand the molecular features that contribute to bitter, sweet and licorice sensation of licorice roots, and whether individual compounds elicit more than one of these sensations. Therefore, a sensomics approach was conducted, followed by purification of the compounds with highest sensory impact, and by synthesis as well as full characterization via HRESIMS, ESIMS/MS and 1D/2D-NMR experiments. This led to the discovery and structure determination of 28 sweet, bitter and licorice tasting key phytochemicals, including two unknown compounds. A combination of sensorial, cell-based and computational analysis revealed distinct structural features, such as spatial arrangement of functional groups in the triterpenoid E-ring, driving to different taste sensations and sweet receptor hTAS1R2/R3 stimulation., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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-G s 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 (Ca 2+ ) 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., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Bitter taste facilitates the detection of potentially harmful substances and is perceived via bitter taste receptors (TAS2Rs) expressed on the tongue and oral cavity in vertebrates. In primates, TAS2R16 specifically recognizes β-glucosides, which are important in cyanogenic plants' use of cyanide as a feeding deterrent. In this study, we performed cell-based functional assays for investigating the sensitivity of TAS2R16 to β-glucosides in three species of bamboo lemurs ( Prolemur simus, Hapalemur aureus and H. griseus ), which primarily consume high-cyanide bamboo. TAS2R16 receptors from bamboo lemurs had lower sensitivity to β-glucosides, including cyanogenic glucosides, than that of the closely related ring-tailed lemur ( Lemur catta ). Ancestral reconstructions of TAS2R16 for the bamboo-lemur last common ancestor (LCA) and that of the Hapalemur LCA showed an intermediate sensitivity to β-glucosides between that of the ring-tailed lemurs and bamboo lemurs. Mutagenetic analyses revealed that P. simus and H. griseus had separate species - specific substitutions that led to reduced sensitivity. These results indicate that low sensitivity to β-glucosides at the cellular level-a potentially adaptive trait for feeding on cyanogenic bamboo-evolved independently after the Prolemur - Hapalemur split in each species.

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 D 2 O from H 2 O 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 D 2 O over H 2 O, 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 D 2 O but not by H 2 O. Lactisole, which is a known sweetness inhibitor acting via the TAS1R3 monomer of the TAS1R2/TAS1R3, suppresses the sweetness of D 2 O in human sensory tests, as well as the calcium release elicited by D 2 O 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.

Objectives: To 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., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In a preregistered, cross-sectional study, we investigated whether olfactory loss is a reliable predictor of COVID-19 using a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n = 4148) or negative (C19-; n = 546) COVID-19 laboratory test outcome. Logistic regression models identified univariate and multivariate predictors of COVID-19 status and post-COVID-19 olfactory recovery. Both C19+ and C19- groups exhibited smell loss, but it was significantly larger in C19+ participants (mean ± SD, C19+: -82.5 ± 27.2 points; C19-: -59.8 ± 37.7). Smell loss during illness was the best predictor of COVID-19 in both univariate and multivariate models (ROC AUC = 0.72). Additional variables provide negligible model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms (e.g., fever). Olfactory recovery within 40 days of respiratory symptom onset was reported for ~50% of participants and was best predicted by time since respiratory symptom onset. We find that quantified smell loss is the best predictor of COVID-19 amongst those with symptoms of respiratory illness. To aid clinicians and contact tracers in identifying individuals with a high likelihood of having COVID-19, we propose a novel 0-10 scale to screen for recent olfactory loss, the ODoR-19. We find that numeric ratings ≤2 indicate high odds of symptomatic COVID-19 (4 < OR < 10). Once independently validated, this tool could be deployed when viral lab tests are impractical or unavailable., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.

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., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Web search tools are widely used by the general public to obtain health-related information, and analysis of search data is often suggested for public health monitoring. We analyzed popularity of searches related to smell loss and taste loss, recently listed as symptoms of COVID-19. Searches on sight loss and hearing loss, which are not considered as COVID-19 symptoms, were used as control. Google Trends results per region in Italy or state in the US were compared to COVID-19 incidence in the corresponding geographical areas. The COVID-19 incidence did not correlate with searches for non-symptoms, but in some weeks had high correlation with taste and smell loss searches, which also correlated with each other. Correlation of the sensory symptoms with new COVID-19 cases for each country as a whole was high at some time points, but decreased (Italy) or dramatically fluctuated over time (US). Smell loss searches correlated with the incidence of media reports in the US. Our results show that popularity of symptom searches is not reliable for pandemic monitoring. Awareness of this limitation is important during the COVID-19 pandemic, which continues to spread and to exhibit new clinical manifestations, and for potential future health threats.

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., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Sweet taste is a cue for calorie-rich food and is innately attractive to animals, including humans. In the context of modern diets, attraction to sweetness presents a significant challenge to human health. Most known sugars and sweeteners bind to the Venus Fly Trap domain of T1R2 subunit of the sweet taste heterodimer. Because the sweet taste receptor structure has not been experimentally solved yet, a possible approach to finding sweet molecules is virtual screening using compatibility of candidate molecules to homology models of sugar-binding site. Here, the constructed structural models, docking and scoring schemes were validated by their ability to rank known sweet-tasting compounds higher than properties-matched random molecules. The best performing models were next used in virtual screening, retrieving recently patented sweeteners and providing novel predictions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Rhodopsin is a light receptor comprised of an opsin protein and a light-sensitive retinal chromophore. Despite more than a century of scrutiny, there is no evidence that opsins function in chemosensation. Here, we demonstrate that three Drosophila opsins, Rh1, Rh4, and Rh7, are needed in gustatory receptor neurons to sense a plant-derived bitter compound, aristolochic acid (ARI). The gustatory requirements for these opsins are light-independent and do not require retinal. The opsins enabled flies to detect lower concentrations of aristolochic acid by initiating an amplification cascade that includes a G-protein, phospholipase Cβ, and the TRP channel, TRPA1. In contrast, responses to higher levels of the bitter compound were mediated through direct activation of TRPA1. Our study reveals roles for opsins in chemosensation and raise questions concerning the original roles for these classical G-protein-coupled receptors., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

This study aimed at identifying whether the bitter-tasting amino acids l-arginine (l-ARG) and l-isoleucine (l-ILE) differentially regulate mechanisms of gastric acid secretion in human parietal cells (HGT-1 cells) via activation of bitter taste sensing receptors (T2Rs). In a first set of experiments, involvement of T2Rs in l-ARG and l-ILE-modulated proton secretion was demonstrated by co-treatment of HGT-1 cells with T2R antagonists. Subsequent whole genome screenings by means of cDNA arrays revealed T2R1 as a prominent target for both amino acids. Next, the functional role of T2R1 was verified by means of a T2R1 CRISPR-Cas9 knock-out approach. Here, the effect of l-ARG on proton secretion decreased by 65.7 ± 21.9% and the effect of l-ILE increased by 93.2 ± 24.1% in HGT-1 T2R1 ko versus HGT-1 wt cells ( p < 0.05). Overall, our results indicate differential effects of l-ARG and l-ILE on proton secretion in HGT-1 cells and our molecular docking studies predict distinct binding for these amino acids in the binding site of T2R1. Further studies will elucidate whether the mechanism of differential effects involves structure-specific ligand-biased signaling of T2R1 or additional cellular targets.

Human bitter taste receptors (TAS2Rs) are a subfamily of 25 G protein-coupled receptors that mediate bitter taste perception. TAS2R14 is the most broadly tuned bitter taste receptor, recognizing a range of chemically diverse agonists with micromolar-range potency. The receptor is expressed in several extra-oral tissues and is suggested to have physiological roles related to innate immune responses, male fertility, and cancer. Higher potency ligands are needed to investigate TAS2R14 function and to modulate it for future clinical applications. Here, a structure-based modeling approach is described for the design of TAS2R14 agonists beginning from flufenamic acid, an approved non-steroidal anti-inflammatory analgesic that activates TAS2R14 at sub-micromolar concentrations. Structure-based molecular modeling was integrated with experimental data to design new TAS2R14 agonists. Subsequent chemical synthesis and in vitro profiling resulted in new TAS2R14 agonists with improved potency compared to the lead. The integrated approach provides a validated and refined structural model of ligand-TAS2R14 interactions and a general framework for structure-based discovery in the absence of closely related experimental structures.

Detection and identification of bitter compounds draw great attention in pharmaceutical and food industry. Several well-known agonists of specific bitter taste receptors have been found to exhibit anti-cancer effects. For example, N-C=S-containing compounds, such as allyl-isothiocyanates, have shown cancer chemo-preventive effects. It is worth noting that human T2R38 receptor is specific for compounds containing N-C=S moiety. Here, a bioinspired cell-based bioelctronic tongue (BioET) is developed for the high-specificity isothiocyanate-induced bitter detection, utilizing human Caco-2 cells as a primary sensing element and interdigitated impedance sensor as a secondary transducer. As an intestinal carcinoma cell line, Caco-2 endogenously expresses human bitter receptor T2R38, and the activation of T2R38 induces the changes of cellular morphology which can be detected by electric cell-substrate impedance sensing (ECIS). After configuration and optimization of parameters including timing of compound administration and cell density, quantitative bitter evaluation models were built for two well-known bitter compounds, phenylthiocarbamide (PTC) and propylthiouracil (PROP). The bitter specific detection of this BioET is inhibited by probenecid and U-73122, and is not elicited by other taste modalities or bitter ligands that do not activate T2R38. Moreover, by combining different computational tools, we designed a ligand-based virtual screening (LBVS) protocol to select ligands that are likely to activate T2R38 receptor. Three computationally predicted agonists of T2R38 were selected using the LBVS protocol, and the BioET presented response to the predicted agonists, validating the capability of the LBVS protocol. This study suggests this unique cell-based BioET paves a general and promising way to specifically detect N-C=S-containing compounds that can be used for pharmaceutical study and drug development., (Copyright © 2019 Elsevier B.V. All rights reserved.)

"Bitter" and "sweet" are frequently framed in opposition, both functionally and metaphorically, in regard to affective responses, emotion, and nutrition. This oppositional relationship is complicated by the fact that some molecules are simultaneously bitter and sweet. In some cases, a small chemical modification, or a chirality switch, flips the taste from sweet to bitter. Molecules humans describe as bitter are recognized by a 25-member subfamily of class A G-protein coupled receptors (GPCRs) known as TAS2Rs. Molecules humans describe as sweet are recognized by a TAS1R2/TAS1R3 heterodimer of class C GPCRs. Here we characterize the chemical space of bitter and sweet molecules: the majority of bitter compounds show higher hydrophobicity compared to sweet compounds, while sweet molecules have a wider range of sizes. Importantly, recent evidence indicates that TAS1Rs and TAS2Rs are not limited to the oral cavity; moreover, some bitterants are pharmacologically promiscuous, with the hERG potassium channel, cytochrome P450 enzymes, and carbonic anhydrases as common off-targets. Further focus on polypharmacology may unravel new physiological roles for tastant molecules., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromolecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop is used here to provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of allostery gained from computational and experimental analyses of real protein systems and model systems. The main conceptual frameworks instrumental in driving the field are discussed. We illustrate the role of these frameworks in illuminating molecular mechanisms and explaining cellular processes, and describe some of their promising practical applications in engineering molecular sensors and informing drug design efforts., (Copyright © 2019. Published by Elsevier Ltd.)

A respected number of drugs suffer from bitter taste which results in patient incompliance. With the aim of solving the bitterness of guaifenesin, dimethyl maleate, maleate, glutarate, succinate, and dimethyl succinate prodrugs were designed and synthesized. Molecular orbital methods were utilized for the design of the ester prodrugs. The density functional theory (DFT) calculations revealed that the hydrolysis efficiency of the synthesized prodrugs is significantly sensitive to the pattern of substitution on C=C bond and distance between the nucleophile and the electrophile. The hydrolysis of the prodrugs was largely affected by the pH of the medium. The experimental t 1/2 for the hydrolysis of guaifenesin dimaleate ester prodrugs in 1N HCl was the least and for guaifenesin dimethyl succinate was the highest. Functional heterologous expression of TAS2R14, a broadly tuned bitter taste receptor responding to guaifenesin, and experiments using these prodrugs revealed that, while some of the prodrugs still activated the receptor similarly or even stronger than the parent substance, succinate derivatization resulted in the complete loss of receptor responses. The predicted binding modes of guaifenesin and its prodrugs to the TAS2R14 homology model suggest that the decreased activity of the succinate derivatives may be caused by a clash with Phe247., (© 2018 John Wiley & Sons A/S.)

BitterDB (http://bitterdb.agri.huji.ac.il) was introduced in 2012 as a central resource for information on bitter-tasting molecules and their receptors. The information in BitterDB is frequently used for choosing suitable ligands for experimental studies, for developing bitterness predictors, for analysis of receptors promiscuity and more. Here, we describe a major upgrade of the database, including significant increase in content as well as new features. BitterDB now holds over 1000 bitter molecules, up from the initial 550. When available, quantitative sensory data on bitterness intensity as well as toxicity information were added. For 270 molecules, at least one associated bitter taste receptor (T2R) is reported. The overall number of ligand-T2R associations is now close to 800. BitterDB was extended to several species: in addition to human, it now holds information on mouse, cat and chicken T2Rs, and the compounds that activate them. BitterDB now provides a unique platform for structure-based studies with high-quality homology models, known ligands, and for the human receptors also data from mutagenesis experiments, information on frequently occurring single nucleotide polymorphisms and links to expression levels in different tissues.

Background: In humans, bitterness perception is mediated by ~25 bitter taste receptors present in the oral cavity. Among these receptors three, TAS2R10, TAS2R14 and TAS2R46, exhibit extraordinary wide agonist profiles and hence contribute disproportionally high to the perception of bitterness. Perhaps the most broadly tuned receptor is the TAS2R14, which may represent, because of its prominent expression in extraoral tissues, a receptor of particular importance for the physiological actions of bitter compounds beyond taste., Methods: To investigate how the architecture and composition of the TAS2R14 binding pocket enables specific interactions with a complex array of chemically diverse bitter agonists, we carried out homology modeling and ligand docking experiments, subjected the receptor to point-mutagenesis of binding site residues and performed functional calcium mobilization assays., Results: In total, 40 point-mutated receptor constructs were generated to investigate the contribution of 19 positions presumably located in the receptor's binding pocket to activation by 7 different TAS2R14 agonists. All investigated positions exhibited moderate to pronounced agonist selectivity., Conclusions: Since numerous modifications of the TAS2R14 binding pocket resulted in improved responses to individual agonists, we conclude that this bitter taste receptor might represent a suitable template for the engineering of the agonist profile of a chemoreceptive receptor., General Significance: The detailed structure-function analysis of the highly promiscuous and widely expressed TAS2R14 suggests that this receptor must be considered as potentially frequent target for known and novel drugs including undesired off-effects., (Copyright © 2018 Elsevier B.V. All rights reserved.)

[This corrects the article DOI: 10.3389/fmolb.2018.00009.].

Dramatic increase in NaCl consumption lead to sodium intake beyond health guidelines. KCl substitution helps reduce sodium intake but results in a bitter-metallic off-taste. Two disaccharides, trehalose and sucrose, were tested in order to untangle the chemical (increase in effective concentration of KCl due to sugar addition) from the sensory effects. The bitter-metallic taste of KCl was reduced by these sugars, while saltiness was enhanced or unaltered. The perceived sweetness of sugar, regardless of its type and concentration, was an important factor in KCl taste modulation. Though KCl was previously shown to increase the chemical activity of trehalose but not of sucrose, we found that it suppressed the perceived sweetness of both sugars. Therefore, sensory integration was the dominant factor in the tested KCl-sugar combinations., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The 25 human bitter taste receptors (hT2Rs) recognize thousands of structurally and chemically diverse bitter substances. The binding modes of human bitter taste receptors hT2R10 and hT2R46, which are responsible for strychnine recognition, were previously established using site-directed mutagenesis, functional assays, and molecular modeling. Here we construct a phylogenetic tree and reconstruct ancestral sequences of the T2R10 and T2R46 clades. We next analyze the binding sites in view of experimental data to predict their ability to recognize strychnine. This analysis suggests that the common ancestor of hT2R10 and hT2R46 is unlikely to bind strychnine in the same mode as either of its two descendants. Estimation of relative divergence times shows that hT2R10 evolved earlier than hT2R46. Strychnine recognition was likely acquired first by the earliest common ancestor of the T2R10 clade before the separation of primates from other mammals, and was highly conserved within the clade. It was probably independently acquired by the common ancestor of T2R43-47 before the homo-ape speciation, lost in most T2Rs within this clade, but enhanced in the hT2R46 after humans diverged from the rest of primates. Our findings suggest hypothetical strychnine T2R receptors in several species, and serve as an experimental guide for further study. Improved understanding of how bitter taste receptors acquire the ability to be activated by particular ligands is valuable for the development of sensors for bitterness and for potential toxicity.

Bitter taste is innately aversive and thought to protect against consuming poisons. Bitter taste receptors (Tas2Rs) are G-protein coupled receptors, expressed both orally and extra-orally and proposed as novel targets for several indications, including asthma. Many clinical drugs elicit bitter taste, suggesting the possibility of drugs re-purposing. On the other hand, the bitter taste of medicine presents a major compliance problem for pediatric drugs. Thus, efficient tools for predicting, measuring and masking bitterness of active pharmaceutical ingredients (APIs) are required by the pharmaceutical industry. Here we highlight the BitterDB database of bitter compounds and survey the main computational approaches to prediction of bitter taste based on compound's chemical structure. Current in silico bitterness prediction methods provide encouraging results, can be constantly improved using growing experimental data, and present a reliable and efficient addition to the APIs development toolbox., (Copyright © 2017 Elsevier B.V. All rights reserved.)