Zhang B, Salituro G, Szalkowski D, Li Z, Zhang Y, Royo I, Vilella D, Díez M T, Pelaez F, Ruby C, Kendall R L, Mao X, Griffin P, Calaycay J, Zierath J R, Heck J V, Smith R G, Moller D E
Department of Molecular Endocrinology, Merck Research Laboratories, R80W250, Post Office Box 2000, Rahway, NJ 07065, USA.
Science. 1999 May 7;284(5416):974-7. doi: 10.1126/science.284.5416.974.
Insulin elicits a spectrum of biological responses by binding to its cell surface receptor. In a screen for small molecules that activate the human insulin receptor tyrosine kinase, a nonpeptidyl fungal metabolite (L-783,281) was identified that acted as an insulin mimetic in several biochemical and cellular assays. The compound was selective for insulin receptor versus insulin-like growth factor I (IGFI) receptor and other receptor tyrosine kinases. Oral administration of L-783,281 to two mouse models of diabetes resulted in significant lowering in blood glucose levels. These results demonstrate the feasibility of discovering novel insulin receptor activators that may lead to new therapies for diabetes.
胰岛素通过与细胞表面受体结合引发一系列生物学反应。在一项筛选激活人胰岛素受体酪氨酸激酶的小分子的研究中，鉴定出一种非肽类真菌代谢物（L-783,281），它在多种生化和细胞试验中表现为胰岛素模拟物。该化合物对胰岛素受体具有选择性，相对于胰岛素样生长因子I（IGF-I）受体和其他受体酪氨酸激酶而言。对两种糖尿病小鼠模型口服L-783,281可导致血糖水平显著降低。这些结果证明了发现新型胰岛素受体激活剂的可行性，这些激活剂可能会带来糖尿病的新疗法。
