Inhibition of Bitter Taste from Oral Tenofovir Alafenamide.

Autor:	Schwiebert E; Discovery Biomed, Birmingham, Alabama (E.S., J.S.); Monell Chemical Senses Center, Philadelphia, Pennsylvania (Y.W., R.X., K.C., L.J.F., N.R., M.H.O., R.F.M., C.M.C., N.E.R., P.J., P.A.S.B.); and Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey (P.A.S.B.) erik@discoverybiomed.com., Wang Y; Discovery Biomed, Birmingham, Alabama (E.S., J.S.); Monell Chemical Senses Center, Philadelphia, Pennsylvania (Y.W., R.X., K.C., L.J.F., N.R., M.H.O., R.F.M., C.M.C., N.E.R., P.J., P.A.S.B.); and Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey (P.A.S.B.)., Xi R; Discovery Biomed, Birmingham, Alabama (E.S., J.S.); Monell Chemical Senses Center, Philadelphia, Pennsylvania (Y.W., R.X., K.C., L.J.F., N.R., M.H.O., R.F.M., C.M.C., N.E.R., P.J., P.A.S.B.); and Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey (P.A.S.B.)., Choma K; Discovery Biomed, Birmingham, Alabama (E.S., J.S.); Monell Chemical Senses Center, Philadelphia, Pennsylvania (Y.W., R.X., K.C., L.J.F., N.R., M.H.O., R.F.M., C.M.C., N.E.R., P.J., P.A.S.B.); and Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey (P.A.S.B.)., Streiff J; Discovery Biomed, Birmingham, Alabama (E.S., J.S.); Monell Chemical Senses Center, Philadelphia, Pennsylvania (Y.W., R.X., K.C., L.J.F., N.R., M.H.O., R.F.M., C.M.C., N.E.R., P.J., P.A.S.B.); and Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey (P.A.S.B.)., Flammer LJ; Discovery Biomed, Birmingham, Alabama (E.S., J.S.); Monell Chemical Senses Center, Philadelphia, Pennsylvania (Y.W., R.X., K.C., L.J.F., N.R., M.H.O., R.F.M., C.M.C., N.E.R., P.J., P.A.S.B.); and Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey (P.A.S.B.)., Rivers N; Discovery Biomed, Birmingham, Alabama (E.S., J.S.); Monell Chemical Senses Center, Philadelphia, Pennsylvania (Y.W., R.X., K.C., L.J.F., N.R., M.H.O., R.F.M., C.M.C., N.E.R., P.J., P.A.S.B.); and Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey (P.A.S.B.)., Ozdener MH; Discovery Biomed, Birmingham, Alabama (E.S., J.S.); Monell Chemical Senses Center, Philadelphia, Pennsylvania (Y.W., R.X., K.C., L.J.F., N.R., M.H.O., R.F.M., C.M.C., N.E.R., P.J., P.A.S.B.); and Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey (P.A.S.B.)., Margolskee RF; Discovery Biomed, Birmingham, Alabama (E.S., J.S.); Monell Chemical Senses Center, Philadelphia, Pennsylvania (Y.W., R.X., K.C., L.J.F., N.R., M.H.O., R.F.M., C.M.C., N.E.R., P.J., P.A.S.B.); and Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey (P.A.S.B.)., Christensen CM; Discovery Biomed, Birmingham, Alabama (E.S., J.S.); Monell Chemical Senses Center, Philadelphia, Pennsylvania (Y.W., R.X., K.C., L.J.F., N.R., M.H.O., R.F.M., C.M.C., N.E.R., P.J., P.A.S.B.); and Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey (P.A.S.B.)., Rawson NE; Discovery Biomed, Birmingham, Alabama (E.S., J.S.); Monell Chemical Senses Center, Philadelphia, Pennsylvania (Y.W., R.X., K.C., L.J.F., N.R., M.H.O., R.F.M., C.M.C., N.E.R., P.J., P.A.S.B.); and Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey (P.A.S.B.)., Jiang P; Discovery Biomed, Birmingham, Alabama (E.S., J.S.); Monell Chemical Senses Center, Philadelphia, Pennsylvania (Y.W., R.X., K.C., L.J.F., N.R., M.H.O., R.F.M., C.M.C., N.E.R., P.J., P.A.S.B.); and Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey (P.A.S.B.) pjiang@monell.org., Breslin PAS; Discovery Biomed, Birmingham, Alabama (E.S., J.S.); Monell Chemical Senses Center, Philadelphia, Pennsylvania (Y.W., R.X., K.C., L.J.F., N.R., M.H.O., R.F.M., C.M.C., N.E.R., P.J., P.A.S.B.); and Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey (P.A.S.B.) pbreslin@monell.org.
Jazyk:	angličtina
Zdroj:	Molecular pharmacology [Mol Pharmacol] 2021 May; Vol. 99 (5), pp. 319-327. Date of Electronic Publication: 2021 Apr 06.
DOI:	10.1124/molpharm.120.000071
Abstrakt:	Children have difficulty swallowing capsules. Yet, when presented with liquid formulations, children often reject oral medications due to their intense bitterness. Presently, effective strategies to identify methods, reagents, and tools to block bitterness remain elusive. For a specific bitter-tasting drug, identification of the responsible bitter receptors and discovery of antagonists for those receptors can provide a method to block perceived bitterness. We have identified a compound (6-methylflavone) that can block responses to an intensely bitter-tasting anti-human immunodeficiency virus (HIV) drug, tenofovir alafenamide (TAF), using a primary human taste bud epithelial cell culture as a screening platform. Specifically, TAS2R39 and TAS2R1 are the main type 2 taste receptors responding to TAF observed via heterologously expressing specific TAS2R receptors into HEK293 cells. In this assay, 6-methylflavone blocked the responses of TAS2R39 to TAF. In human sensory testing, 8 of 16 subjects showed reduction in perceived bitterness of TAF after pretreating (or "prerinsing") with 6-methylflavone and mixing 6-methylflavone with TAF. Bitterness was completely and reliably blocked in two of these subjects. These data demonstrate that a combined approach of human taste cell culture-based screening, receptor-specific assays, and human psychophysical testing can successfully discover molecules for blocking perceived bitterness of pharmaceuticals, such as the HIV therapeutic TAF. Our hope is to use bitter taste blockers to increase medical compliance with these vital medicines. SIGNIFICANCE STATEMENT: Identification of a small molecule that inhibits bitter taste from tenofovir alafenamide may increase the compliance in treating children with human immunodeficiency virus infections. (Copyright © 2021 The Author(s).)
Databáze:	MEDLINE
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