Background
AY 9944 dihydrochloride is a selective inhibitor of Δ7-sterol reductase with IC50 value of 13 nM [1].
Δ7-sterol reductase (Dhcr7) is an enzyme and plays an important role in catalyzing the production of cholesterol from 7-Dehydrocholesterol through using NADPH [2, 3].
AY 9944 dihydrochloride is a potentΔ7-sterol reductase inhibitor and has higher inhibition thanΔ7-sterol reductase inhibitor BM15766 and triparanol. When tested with Saccharomyces cerevisiae expressed cDNA without an N-terminal 9E10 c-myc epitope (mycD7-ORF) and 5’ noncoding region (D7-ORF), AY 9944 dihydrochloride exhibited highly inhibition on D7-ORF (recombinant humanΔ7-sterol reductase ) with IC50 value of 13 nM [1]. In PBMCs isolated from AIDS patients, AY 9944 treatment exhibited ability to restore the normal mitogenic responses and cytokine profiles [2].
In Sprague-Dawley rats model of Smith-Lemli-Opitz syndrome, administration of AY9944 elevated 7-DHC expression and reduced cholesterol in all biological tissues by inhibitingΔ7-sterol reductase [3].
参考文献:
[1].? Moebius, F.F., et al., Molecular cloning and expression of the human delta7-sterol reductase. Proc Natl Acad Sci U S A, 1998. 95(4): p. 1899-902.
[2].? Achour, A., et al., Restoration of immune response by a cationic amphiphilic drug (AY 9944) in vitro: a new approach To chemotherapy against human immunodeficiency virus type 1. Antimicrob Agents Chemother, 1998. 42(10): p. 2482-91.
[3].?? Xu, L., et al., Novel oxysterols observed in tissues and fluids of AY9944-treated rats: a model for Smith-Lemli-Opitz syndrome. J Lipid Res, 2011. 52(10): p. 1810-20.
Protocol
| Cell experiment [1]: |
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Cell lines
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PBMCs
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Preparation method
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The solubility of this compound in sterile water is 50 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months.
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Reacting condition
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3 × 10-6 M
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Applications
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In HIV-1-infected PBMCs, AY 9944 Dihydrochloride restored mitogen-induced as well as recall antigen- and superantigen-induced proliferation. After 2-week treatment, the percentage of dead CD4+ cells in HIV-1-infected cultures was comparable that in uninfected culture. AY 9944 Dihydrochloride also stimulated IL-12 and interferon-γ production by 2 ~ 12 folds.
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| Animal experiment [2]: |
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Animal models
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SD rats
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Dosage form
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25 mg/kg; s.c.
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Applications
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The relative enrichment of sterol in rafts from AY 9944 Dihydrochloride-treated rat brains (average 7.85 folds) was similar to that from the control group (5.44 folds), which implied that 7-dehydrocholesterol (7DHC) promoted raft formation in a similar way as cholesterol did. However, the protein profiles of rafts from AY 9944 Dihydrochloride-treated rat brains were markedly different from those from the control group.
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
[1]. Achour, A., et al., Restoration of immune response by a cationic amphiphilic drug (AY 9944) in vitro: a new approach To chemotherapy against human immunodeficiency virus type 1. Antimicrob Agents Chemother, 1998. 42(10): p. 2482-91.
[2]. Keller RK, Arnold TP, Fliesler SJ. Formation of 7-dehydrocholesterol-containing membrane rafts in vitro and in vivo, with relevance to the Smith-Lemli-Opitz syndrome. J Lipid Res. 2004 Feb;45(2):347-55.
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