ABCC4 p.Met184Val
Predicted by SNAP2: | A: N (78%), C: N (82%), D: N (66%), E: N (82%), F: N (57%), G: N (78%), H: N (82%), I: N (87%), K: N (93%), L: N (87%), N: N (87%), P: N (72%), Q: D (71%), R: D (80%), S: N (87%), T: N (53%), V: N (93%), W: D (59%), Y: N (61%), |
Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N, |
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[hide] Retention of metabolites of 2',3'-didehydro-3'-deo... Antimicrob Agents Chemother. 2009 Aug;53(8):3317-24. Epub 2009 May 26. Wang X, Tanaka H, Baba M, Cheng YC
Retention of metabolites of 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine, a novel anti-human immunodeficiency virus type 1 thymidine analog, in cells.
Antimicrob Agents Chemother. 2009 Aug;53(8):3317-24. Epub 2009 May 26., [PMID:19470503]
Abstract [show]
2',3'-Didehydro-3'-deoxy-4'-ethynylthymidine (4'-Ed4T), a novel thymidine analog, has more potent anti-human immunodeficiency virus type 1 (HIV-1) activity than its progenitor, stavudine (d4T). The profile of the intracellular metabolites of 4'-Ed4T was qualitatively similar to that of zidovudine (AZT) but not to that of d4T, while after drug removal it showed more persistent anti-HIV activity than AZT or d4T in cell culture. When CEM cells were exposed to various concentrations of 4'-Ed4T, 4'-Ed4T was efficiently taken up by the cells and was readily phosphorylated to 4'-Ed4T monophosphate (4'-Ed4TMP), 4'-Ed4T diphosphate (4'-Ed4TDP), and 4'-Ed4T triphosphate (4'-Ed4TTP). Most importantly, 4'-Ed4TTP, the active metabolite of 4'-Ed4T, persisted significantly longer than 4'-Ed4TDP and 4'-Ed4TMP after drug removal. We further investigated the efflux profiles of 4'-Ed4T in the comparison with those of AZT in CEM cells. After drug removal, both 4'-Ed4T and AZT were effluxed from the cells in a time- and temperature-dependent manner. However, the efflux of 4'-Ed4T from cells was much less efficient than that of AZT. 4'-Ed4T was effluxed from cells only in its nucleoside form, while AZT was effluxed from cells in both its nucleoside and monophosphate forms. The mechanism-of-action study showed that the efflux of 4'-Ed4T or AZT nucleoside might be due to unknown nucleoside transporters which were not related to the equilibrative nucleoside transporters, while the efflux of AZT monophosphate might be due to multidrug resistance protein 4 (MRP4/ABCC4). The results demonstrated that no detectable 4'-Ed4TMP efflux and the less efficient efflux of 4'-Ed4T nucleoside from cells might be one of the biochemical determinants of its persistent antiviral activity in cell culture.
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No. Sentence Comment
23 Moreover, 4Ј-Ed4T was found to be active against multidrug-resistant HIV-1 clinical isolates, while a unique pattern of RT resistance mutations (P119S, T165A, and M184V) in the virus was observed under the selection pressure of 4Ј-Ed4T in vitro (13).
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ABCC4 p.Met184Val 19470503:23:169
status: NEW[hide] Novel nucleotide human immunodeficiency virus reve... Antimicrob Agents Chemother. 2009 Jan;53(1):150-6. Epub 2008 Nov 10. Cihlar T, Laflamme G, Fisher R, Carey AC, Vela JE, Mackman R, Ray AS
Novel nucleotide human immunodeficiency virus reverse transcriptase inhibitor GS-9148 with a low nephrotoxic potential: characterization of renal transport and accumulation.
Antimicrob Agents Chemother. 2009 Jan;53(1):150-6. Epub 2008 Nov 10., [PMID:19001108]
Abstract [show]
Accumulation of antiviral nucleotides in renal proximal tubules is controlled by their basolateral uptake via the human renal organic anion transporters type 1 (hOAT1) and 3 (hOAT3) and apical efflux via the multidrug resistance protein 4 (MRP4). GS-9148 is a novel ribose-modified nucleotide human immunodeficiency virus (HIV) reverse transcriptase inhibitor, and its oral prodrug GS-9131 is currently being evaluated in the clinic as an anti-HIV agent. To assess the potential of GS-9148 for nephrotoxicity, its mechanism of renal transport, cytotoxicity, and renal accumulation were explored in vitro and in vivo. In comparison with the acyclic nucleotides cidofovir, adefovir, and tenofovir, GS-9148 showed 60- to 100-fold lower efficiency of transport (V(max)/K(m)) by hOAT1 and was 20- to 300-fold less cytotoxic in cells overexpressing hOAT1, indicating its lower hOAT1-mediated intracellular accumulation and reduced intrinsic cytotoxicity. GS-9148 was also relatively inefficiently transported by hOAT3. Similar to acyclic nucleotides, GS-9148 was a substrate for MRP4 as evidenced by its reduced intracellular retention in cells overexpressing the efflux pump. Consistent with these molecular observations, GS-9148 was inefficiently taken up by fresh human renal cortex tissue in vitro and showed a limited accumulation in kidneys in vivo following oral administration of [(14)C]GS-9131 to dogs. Compared to acyclic nucleotide analogs, GS-9148 was also found to have lower net active tubular secretion in dogs. Collectively, these results suggest that GS-9148 exhibits a low potential for renal accumulation and nephrotoxicity.
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24 Importantly, the parent nucleotide GS-9148 shows a favorable resistance profile and retains its activity against a wide range of nucleoside-resistant HIV-1 variants, including viruses with multiple M184V, K65R, L74V, and thymidine analog mutations in reverse transcriptase (5).
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ABCC4 p.Met184Val 19001108:24:198
status: NEW