P-glycoproteins and uses thereof
AssigneeBecton, Dickinson and Company
InventorsSara Hanscom, Charles Crespi
Life of this patent
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Abstract
The invention pertains to rhesus monkey P-glycoproteins and related P-glycoproteins which include rhesus-specific amino acids, as well as nucleic acids which encode those polypeptides. The present invention also includes fragments and biologically functional variants of the rhesus monkey P-glycoprotein. The invention further relates to methods of using such rhesus monkey P-glycoprotein nucleic acids and polypeptides, especially in methods for determining bioavailability of drugs and for screening for inhibitors of rhesus PGP. Also included are rhesus PGP inhibitors which inhibit rhesus PGP activity by inhibiting the expression or function of rhesus PGP.
Claims42
An isolated nucleic acid molecule selected from the group consisting of
- (a) nucleic acid molecules that code for a rhesus monkey P-glycoprotein and hybridize under stringent conditions to the nucleotide sequence set forth in SEQ ID NO:1;
- (b) degenerate nucleic acids that differ from the biologically isolated nucleic acids in codon sequence due to the degeneracy of the genetic code and
- (c) complements of (a) or (b).
An isolated P-glycoprotein molecule comprising the polypeptide sequence of SEQ ID NO:2.
An isolated P-glycoprotein polypeptide or fragment thereof which comprises at least one amino acid of a rhesus P-glycoprotein selected from the group consisting of amino acids 55, 93, 94, 95, 230, and 234 of SEQ ID NO:2, wherein the P-glycoprotein is identical to a cynomologous P-glycoprotein except for the at least one amino acid of a rhesus P-glycoprotein.
An isolated P-glycoprotein polypeptide or fragment thereof which comprises at least one amino acid of a rhesus P-glycoprotein selected from the group consisting of amino acids 12, 24, 30, 55, 74, 78, 86, 89, 90, 91, 92, 93, 94, 95, 98, 100, 102, 105, 106, 107, 188, 230, 234, 327, 339, 366, 497, 521, 638, 653, 659, 662, 680, 733, 741, 745, 748, 764, 768, 838, 854, 924, 970, 1006, 1030, 1041, 1051, 1106, 1131, 1171 and 1280 of SEQ ID NO:2, wherein the P-glycoprotein is identical to a human P-glycoprotein except for the at least one amino acid of a rhesus P-glycoprotein.
An isolated P-glycoprotein polypeptide or fragment thereof which comprises at least one amino acid of a rhesus P-glycoprotein selected from the group consisting of amino acids 3, 6, 8, 10, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, 26, 28, 29, 30, 31, 36, 38, 48, 52, 55, 56, 64, 74, 78, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 96, 97, 98, 99, 101, 103, 104, 105, 106, 107, 108, 109, 113, 116, 148, 193, 198, 200, 213, 230, 234, 289 322, 327, 330, 348, 366, 398, 451, 455, 456, 468, 473, 497, 521, 533, 634, 644, 645, 651, 653, 658, 659, 667, 668, 675, 676, 677, 678, 686, 690, 692, 694, 695, 697, 704, 708, 718, 732, 733, 737, 745, 746, 748, 757, 760, 768, 838, 915, 921, 924, 943, 944, 947, 969, 970, 971, 973, 975, 984, 1011, 1018, 1026, 1027, 1051, 1096, 1099, 1106, 1131, 1145, 1149, 1150, 1159, 1163, 1166, 1169, 1253, 1271, and 1274 of SEQ ID NO:2, wherein the P-glycoprotein is identical to a dog P-glycoprotein except for the at least one amino acid of a rhesus P-glycoprotein.
A method for predicting the bioavailability of a compound, comprising
- measuring the transmembrane transport of a test compound by a first P-glycoprotein,
- comparing the transmembrane transport of the test compound by the first P-glycoprotein and a second P-glycoprotein to predict the bioavailability of the test compound, wherein the relative amount or rate of transport by the first P-glycoprotein and the second P-glycoprotein is predictive of bioavailability of the test compound.
Dependencies are inferred from the claim text.