Martodam R R, Twumasi D Y, Liener I E, Powers J C, Nishino N, Krejcarek G
Proc Natl Acad Sci U S A. 1979 May;76(5):2128-32. doi: 10.1073/pnas.76.5.2128.
Methods are described for the covalent attachment of succinoyl-Ala-Ala-Pro-ValCH2Cl, an active site-directed inhibitor of human leukocyte elastase (EC 3.4.21.11), to microspheres of human albumin. The insertion of side arms of various lengths revealed that maximum inhibition of this enzyme was obtained when the spacer arm was at least 24.3 A in length. Approximately 30 molecules of the inhibitor could be attached to each molecule of albumin. Such derivatized microspheres were capable of inhibiting approximately one mole of elastase per mole of albumin, which is comparable to the inhibitory activity of alpha 1-antitrypsin. Experiments in vivo in which rats were injected intravenously with radiolabeled microspheres to which the inhibitor had been attached showed a rapid and exclusive uptake by the lungs. About 40--50% of the injected microspheres subsequently remained in the lungs with a half-life of approximately 17 days. These derivatized microspheres thus appear to offer promise as a therapeutic agent for emphysema.
本文描述了将琥珀酰 - 丙氨酸 - 丙氨酸 - 脯氨酸 - 缬氨酸 - CH₂Cl（一种人白细胞弹性蛋白酶（EC 3.4.21.11）的活性位点定向抑制剂）共价连接到人血清白蛋白微球上的方法。插入不同长度的侧链表明，当间隔臂长度至少为24.3 Å时，该酶的抑制作用最大。每分子白蛋白大约可以连接30个抑制剂分子。这种衍生化的微球每摩尔白蛋白能够抑制大约一摩尔弹性蛋白酶，这与α1 - 抗胰蛋白酶的抑制活性相当。在体内实验中，给大鼠静脉注射附着有抑制剂的放射性标记微球，结果显示肺部迅速且特异性地摄取了这些微球。随后，约40 - 50%的注射微球留在肺部，半衰期约为17天。因此，这些衍生化的微球似乎有望成为治疗肺气肿的药物。
