生物活性

Mycophenolic acid is a potent IMPDH inhibitor and the active metabolite of an immunosuppressive drug, used to prevent rejection in organ transplantation. Mycophenolic Acid is an immunosuppressant small molecule isolated as a fermentation product from several Penicillium species. Mycophenolic Acid functions as a potent reversible inhibitor of IMPDH (inosine monophosphate dehydrogenase), leading to a depletion of GMP in the cell and interruption of the de novo synthesis of purines necessary for lymphocyte proliferation. This powerful immunosuppressant property has been exploited in studies on organ transplant survival, rhuematoid arthritis, and psoriasis. Derivitization of Mycophenolic Acid to the morpholinoethyl ester, known as Mycophenolate mofetil, presents a greater bioavailability for the active compound.Immunosuppressive agent with antiviral and antitumor effects in vitro and in vivo. Potently inhibits inosine monophosphate dehydrogenase, thus inhibiting de novo GTP synthesis leading to decreased RNA and DNA synthesis. Reversibly inhibits proliferation of T and B lymphocytes and antibody formation.

体外研究

体内研究

激酶实验

细胞实验

Viruses, cells, and compounds[1]

These viruses were propagated in MDCK cellsbefore use. Mycophenolic acid (MPA), prepared as 100mM stocks in 100% dimethylsulfoxide DMSO) and zanamivir, prepared as 25mM stocks in water and were storedat -20^oCuntil use. Working solutions of MPA and zanamivir were prepared on the day of experiment.

Cytotoxicityassay

The cytotoxicity of MPA and zanamivir inMDCK cells was determined using MTT assay according to the manufacturer’s instruction.

Timeof addition experiment using cell viability assay

Influenza viruses at a multiplicity ofinfection (MOI) of 0.0001 were inoculated onto MDCK cells in minimum essentialmedium (MEM) with 2μg/ml of tosylsulfonyl phenylalanyl chloromethyl ketone (TPCK)-treatedtrypsin which specifically cleaves lysine and arginine residue. Afterincubation at 37^oC for 1 h, non-attached viruses were removed bywashing the cells twice in serum-free MEM. The monolayer cells were maintainedin MEM with 2μg/ml of TPCKtreated trypsin. MPA in fourfold dilutions was addedto the cells at predetermined time points before or after virus infection.Infected cells were incubated at 35^oC. The cells were examined dailyfor cytopathic effects thereafter, and the viral loads and MTT were determinedafter 3 days of incubation.

动物实验

Reagents[2]

Stock of MPA was dissolved in DMSO and IFN-α 2awas dissolved in water. All agents were stored in 15μl aliquotsand frozen at –20 ^oC. Guanosine was diluted to 1 mM in PBS and storedat -20 ^oC.

HCVMouse Model

Huh7-ET HCV replicon cells and control Huh7cells constitutively expressing luciferase gene (1 x 10⁶ cells in200μL phosphate-buffered saline [PBS]) were simultaneously engraftedinto the right and left flanks of 8-week-old female NOD/ LtSz-scid/scid(NOD/SCID) mice. After overnight recovery, mice were intraperitoneally injectedwith 100μL of 50 mg/mL D-luciferin potassium salt dissolved in PBS. After10minutes the pretreatment luciferase activity was measured in living mice usingan IVIS camera under anesthesia by 1.5% isoflurane inhalation. Immediately aftermeasurement, 50 mg/kg body weight of MPA (in200μL) wasintraperitoneally injected. Control animals were intraperitoneally injectedwith PBS/10%DMSO as vehicle control. Twenty-four hours after injection,luciferase activity was measured again as a posttreatment value.

不同实验动物依据体表面积的等效剂量转换表（数据来源于FDA指南）

例如，已知某工具药用于小鼠的剂量为88 mg/kg , 则用于大鼠的剂量换算方法：将88 mg/kg 乘以小鼠的Km系数（3），再除以大鼠的Km系数（6），得到该药物用于大鼠的等效剂量44 mg/kg。

参考文献

[1] To KK MK, Chan AS, Cheung NN, Wang P, Lui YM, Chan JF, Chen H, Chan KH, Kao RY, Yuen KY. Mycophenolic acid, an immunomodulator, has potent and broad-spectrum in vitro antiviral activity against pandemic, seasonal and avian influenza viruses affecting humans. J Gen Virol. 2016;97(8):1807-1817.
[2] Pan Q dRP, Metselaar HJ, Kwekkeboom J, de Jonge J, Tilanus HW, Janssen HL, van der Laan LJ. Mycophenolic acid augments interferon-stimulated gene expression and inhibits hepatitis C Virus infection in vitro and in vivo. Hepatology. 2012;55(6):1673-1683.

体内溶解度

Clinical Trial Information ( data from http://clinicaltrials.gov )

注：以上所有数据均来自公开文献，并不保证对所有实验均有效，数据仅供参考。

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