Binding of thalidomide to alpha1-acid glycoprotein may be involved in its inhibition of tumor necrosis factor alpha production.

In addition to its well known sedative and teratogenic effects, thalidomide also possesses potent immunomodulatory and antiinflammatory activities, being most effective against leprosy and chronic graft-versus-host disease. The immunomodulatory activity of thalidomide has been ascribed to the selective inhibition of tumor necrosis factor alpha from monocytes. The molecular mechanism for the immunomodulatory effect of thalidomide remains unknown. To elucidate this mechanism, we synthesized an active photoaffinity label of thalidomide as a probe to identify the molecular target of the drug. Using the probe, we specifically labeled a pair of proteins of 43-45 kDa with high acidity from bovine thymus extract. Purification of these proteins and partial peptide sequence determination revealed them to be alpha1-acid glycoprotein (AGP). We show that the binding of thalidomide photoaffinity label to authentic human AGP is competed with both thalidomide and the nonradioactive photoaffinity label at concentrations comparable to those required for inhibition of production of tumor necrosis factor alpha from human monocytes, suggesting that AGP may be involved in the immunomodulatory activity of thalidomide.

除了其众所周知的镇静和致畸作用外，沙利度胺还具有强大的免疫调节和抗炎活性，对麻风病和慢性移植物抗宿主病最为有效。沙利度胺的免疫调节活性归因于对单核细胞肿瘤坏死因子α的选择性抑制。沙利度胺免疫调节作用的分子机制仍然未知。为了阐明这一机制，我们合成了一种沙利度胺的活性光亲和标记物作为探针，以确定该药物的分子靶点。利用该探针，我们从牛胸腺提取物中特异性标记了一对具有高酸性的43 - 45 kDa的蛋白质。对这些蛋白质的纯化和部分肽序列测定表明它们是α1 - 酸性糖蛋白（AGP）。我们发现，沙利度胺光亲和标记物与真正的人AGP的结合可被沙利度胺和非放射性光亲和标记物所竞争，其浓度与抑制人单核细胞产生肿瘤坏死因子α所需的浓度相当，这表明AGP可能参与沙利度胺的免疫调节活性。